Vantagens do sequenciamento completo do exoma sobre o imunomapeamento em 67 pacientes brasileiros com epidermólise bolhosa | Anais Brasileiros de Dermatologia (Portuguese)

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As lesões cutâneas geralmente ocorrem por trauma mínimo. Como a membrana basal é frágil e facilmente danificada na EB, há fluxo constante e posterior acúmulo de líquido extracelular na clivagem gerada entre epiderme e derme.No geral, a EB compreende um grupo de doenças congênitas raras causadas por variantes patogênicas em quase 20 genes relacionados à expressão de proteínas relacionadas à aderência da pele, especialmente aquelas localizadas na zona da membrana basal. A prevalência é estimada em aproximadamente 8,22:1.000.000 e a incidência nos EUA é considerada de 19,6:1.000.000 de recém‐nascidos, com números semelhantes em outros países e aparentemente sem grande distinção entre etnias. Mais de 30 tipos diferentes de EB foram descritos, com tentativa recente de dividi‐los em quatro grandes grupos (2020): EB simples (EBS), EB distrófica (EBD), EB juncional (EBJ) e a forma híbrida, também conhecida como síndrome de Kindler (EBK). Tal classificação é baseada principalmente no padrão de herança (autossômica dominante ou recessiva), na gravidade do fenótipo e na análise histopatológica/imunomapeamento.A análise com microscopia eletrônica e, posteriormente, o imunomapeamento a partir de uma biopsia de pele, eram o antigo método de referência para o diagnóstico de EB. Embora ambos consigam identificar o nível cutâneo onde está situada a clivagem da bolha (intradérmica ou subepidérmica) na maioria das vezes, não há indicação certeira do gene afetado e, portanto, do padrão de herança de cada paciente. Além disso, a biopsia de pele é procedimento invasivo (com necessidade de anestesia local e posterior sutura), e quando seus resultados são inconclusivos, muitas vezes há atraso e necessidade de uma segunda amostra, o que pode ser particularmente problemático em pacientes com EB.<a class="elsevierStyleCrossRef" href="#bib0075">3</a>Nesse cenário, a análise molecular tornou‐se ferramenta importante para diagnóstico mais preciso da EB, especialmente dada a recente consolidação e o acesso mais fácil às técnicas de sequenciamento de próxima geração (NGS, do inglês next generation sequencing).<a class="elsevierStyleCrossRefs" href="#bib0080">4–8</a> Aqui são comparados os resultados do imunomapeamento e do WES de uma coorte brasileira de 67 pacientes com EB.MétodoInformações clínicasForam estudados 67 pacientes de 60 famílias com diferentes tipos de EB, todos atendidos na Unidade de Dor e Cuidados Paliativos Pediátricos, na Unidade de Genética do Instituto da Criança e no Departamento de Dermatologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo.Um protocolo clínico foi elaborado considerando história familiar, exame físico e dermatológico, evolução clínica e outros eventos clínicos importantes. Foram coletados o pedigree e feito o registro fotográfico de todas as famílias.Mapeamento por imunofluorescênciaO imunomapeamento consiste em técnica de imunofluorescência indireta aplicada em fragmento de pele contendo uma bolha totalmente preservada, com análise da presença de antígenos na zona da membrana basal por meio da exposição a anticorpos monoclonais fluorescentes. Apenas para lembrar, a imunofluorescência direta é restrita aos casos de EB autoimune adquirida (que não foram avaliados neste estudo) e, portanto, inútil para nossos pacientes com formas hereditárias de EB.A maioria dos pacientes já havia sido submetida ao imunomapeamento no laboratório de Imunopatologia da instituição antes deste projeto. Aqui, os principais anticorpos utilizados foram anticorpo penfigoide bolhoso, anticorpo laminina, anticorpo colágeno tipo IV e anticorpo colágeno tipo VII. Cada um desses anticorpos é encontrado, respectivamente, nos seguintes locais da junção dermoepidérmica: hemidesmossomos, lâmina lúcida, lâmina densa e sublâmina densa.Todas as análises de imunomapeamento foram realizadas e revisadas pelo dermatologista chefe do laboratório de Imunopatologia. Por fim, destaca‐se o fato de que quatro famílias foram incluídas nas etapas finais do estudo e, portanto, não foram submetidas ao imunomapeamento; além disso, havia quatro parentes de três famílias nas quais os casos índices já tinham resultados de imunomapeamento e moleculares disponíveis; portanto, para esses oito pacientes, foi realizada apenas a confirmação molecular.Análise molecular e classificação de variantesO sequenciamento completo do exoma (WES, do inglês whole‐exome sequencing) foi realizado para todas as 60 famílias; amostras de sangue foram coletadas do probando e de seus pais, mas a análise preliminar concentrou‐se principalmente no probando afetado. Após a identificação da(s) variante(s) candidata(s) no índice, a segregação foi então realizada por sequenciamento de Sanger nos pais (geralmente saudáveis); no caso de irmãos afetados, essa abordagem também era realizada. Todos os testes genéticos foram realizados pelos parceiros investigadores japoneses em Yokohama.As variantes foram interpretadas e classificadas de acordo com as diretrizes de interpretação de variantes do American College of Medical Genetics and Genomics (ACMG; 2015). O caso somente foi considerado diagnosticado quando foram observadas variantes patogênicas ou provavelmente patogênicas em um gene associado ao fenótipo do indivíduo estudado, com zigosidade compatível e em padrão de herança adequado.ResultadosAchados clínicosAchados clínicos típicos, como bolhas difusas, estavam presentes na maioria dos pacientes (48 de 67). Os sintomas e a idade de aparecimento eram obviamente variáveis, mas a maioria apresentava lesões cutâneas típicas desde os primeiros dias de vida. Como esperado para doença autossômica, não havia predomínio de gênero, com 34 mulheres e 33 homens no presente grupo. Além disso, ocorreram quatro óbitos entre os casos de EBD recessiva, todos com 20 anos ou menos, falecidos por sepse seguida de falência de múltiplos órgãos.Epidermólise bolhosa distrófica – COL7A1A grande maioria dos pacientes (47/67) apresentava variantes no gene COL7A1 associadas à herança autossômica recessiva; havia apenas três famílias com recorrência e irmãos afetados (total de sete pacientes). Dado que o diagnóstico específico de EB foi sugerido em apenas 29 dos 46 pacientes submetidos ao imunomapeamento nesse subconjunto (essa técnica não estava disponível para cinco indivíduos), a concordância com o WES foi de 63% para esse tipo de EB.De acordo com a literatura, o fenótipo nesses casos tende a ser mais grave; a maioria dos pacientes nasceu a termo com aparecimento de bolhas nos primeiros 2 dias de vida; apenas dois deles nasceram sem unhas; todos referiram prurido intenso, e outros sintomas importantes eram comuns: dor crônica (78%), desnutrição (71,5%), anemia (48,9%), estenose esofágica com necessidade de dilatação (59,6%) e atraso no desenvolvimento (36%). Dentre eles, três pacientes evoluíram com neoplasia maligna de células escamosas, dois deles na região do calcâneo. Como esperado, as quatro mortes em todo o grupo foram de pacientes com EBD recessiva.Por outro lado, quatro dos pacientes com EBD apresentaram variantes no gene COL7A1 associadas a padrão autossômico dominante; todos eram casos esporádicos em suas respectivas famílias. Em contraste com a forma recessiva, os achados clínicos aqui podem ser considerados geralmente leves: as bolhas não apareceram até aproximadamente 2 meses de vida e eram generalizadas em três pacientes, enquanto confinadas às mãos e pés (forma acral) em apenas um indivíduo; havia perda parcial de unhas, mas nenhum paciente apresentou pseudosindactilia.Epidermólise bolhosa simples – KRT5/KRT14/PLECApesar de ser o tipo mais comum de EB, a EBS representou a minoria dos pacientes (15 pacientes, 12 famílias). Dos sete diferentes genes associados a essa forma da doença, foram identificadas mutações apenas nos genes KRT5, KRT14 e PLEC. Considerando que o diagnóstico específico de EBS foi indicado em apenas oito dos 12 pacientes submetidos ao imunomapeamento nesse grupo (três indivíduos não foram investigadas por essa técnica, pois eram familiares do caso índice), a concordância com o WES foi de quase 67% para esse tipo de EB.Dos seis pacientes com variantes do gene KRT5, todos apresentaram bolhas nos primeiros 10 dias de vida, principalmente nas extremidades, acompanhadas de dor crônica, prurido e sudorese; todos apresentavam algum grau de perda ungueal nos dedos das mãos ou dos pés, e um deles também apresentava dentes frágeis, mas nenhum deles apresentava estenose esofágica. Havia quatro famílias com a forma autossômica dominante da doença, enquanto outras duas manifestaram padrão autossômico recessivo. Ainda assim, não houve diferença clínica significante entre os dois padrões de herança.Em relação aos seis pacientes com variantes no gene KRT14, todos também apresentaram bolhas nos primeiros dias de vida e metade manifestou sudorese e anemia na primeira infância, mas curiosamente nenhum se queixou de prurido; nenhum paciente apresentou pseudosindactilia ou milia. Todos manifestaram padrão autossômico dominante, mas três eram da mesma família (pai e dois filhos de mães diferentes).Por fim, havia três pacientes com variantes do gene PLEC, todos manifestando bolhas nas primeiras horas de vida. As lesões ocorreram principalmente nas extremidades, com presença de milia de pequeno grau, mas os pacientes evoluíram com peso e estatura normais; dois deles foram submetidos à dilatação esofágica por estenose e um apresentou pseudosindactilia nos pés. Todas essas famílias manifestaram a forma autossômica recessiva da doença; duas dessas famílias apresentavam mutações em homozigose, enquanto a restante apresentava variantes em heterozigose composta.Epidermólise bolhosa juncional – COL17A1O único caso de EBJ foi uma menina com variantes homozigotas no gene COL17A1, filha de pais consanguíneos; como o imunomapeamento desse caso isolado também indicou EBJ, a correspondência de ambas as técnicas para essa forma da doença foi de 100% para esse tipo de EB. O fenótipo da paciente poderia ser caracterizado como moderado; ela apresentou bolhas desde o terceiro dia de vida e também referia dores crônicas e prurido constante. Aos 16 anos, a paciente apresentava dificuldade para caminhar, acompanhada de anemia leve e desnutrição. O exame dermatológico revelou bolhas localizadas principalmente em áreas com dobras (braços, joelhos, pés), sem milia, e os cabelos eram finos e frágeis; notavelmente, as unhas dos dedos dos pés estavam ausentes.Achados genéticosForam estudados 67 pacientes de 60 famílias com diferentes tipos de EB, todos atendidos no hospital da instituição.Nesse cenário, havia 47 pacientes (43 famílias) com EB recessiva, quatro pacientes com EB dominante, 15 pacientes (12 famílias) com EBS e uma paciente com EBJ. Das 60 variantes diferentes em genes relacionados à EB observadas nos pacientes, 15 nunca foram publicadas na literatura, que seja de conhecimento dos autores: dez associadas à EBD recessiva, três à EBD dominante e duas à EBS. A maioria delas era de mutações nulas (variantes nonsense, frameshift ou site de splice canônico), com apenas três variantes missense. Os detalhes estão descritos nos materiais suplementares.ImunomapeamentoO imunomapeamento estava disponível em 59 desses pacientes; oito do total de 67 pacientes não puderam prosseguir para investigação com biopsia de pele. Houve concordância entre os resultados do imunomapeamento e do exoma em 37 (62%) desses casos, enquanto em 13 (22%) foi provado que o imunomapeamento estava errado pela análise molecular. Além disso, houve nove pacientes (15%) nos quais os resultados do imunomapeamento foram inconclusivos, como mostrado nas <a class="elsevierStyleCrossRefs" href="#tbl1">tabelas 1 e 2</a>. Portanto, de um total de 22 pacientes, o imunomapeamento estabeleceu diagnóstico errado ou nenhum diagnóstico em 37%.<elsevierMultimedia ident="tbl1"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Por fim, foi realizada a análise de concordância quantificada em relação ao imunomapeamento dos 50 pacientes que receberam resultados positivos (38) ou negativos (12), quando comparados com os resultados do WES. Embora o teste Kappa tenda a subestimar o nível de concordância em relação a doenças raras, nesse caso ele foi igual a−0,261 (intervalo de confiança de 95% de−0,388 a−0,135), indicando não haver concordância entre esses dois exames.DiscussãoHouve claro predomínio de EBD (associada à mutação no gene COL7A1), com 51 dos 67 pacientes (76%) apresentando esse tipo de doença, que geralmente representa fenótipo mais grave, principalmente na forma autossômica recessiva. Considerando que os pacientes deste estudo frequentavam o grupo de Dor e Cuidados Paliativos, já era esperada elevada frequência de gravidade; ainda assim, a contagem total de mortes em pacientes com menos de 20 anos se destaca das taxas de mortalidade brasileiras e globais relatadas, talvez indicando a falta de apoio adequado e intenso ao cuidado desses pacientes em alguns hospitais locais. Fora isso, os fenótipos foram semelhantes aos descritos na literatura para cada respectivo gene.Em relação à história familiar, é importante ressaltar que ela mostrou certo viés, visto que 11 das 60 famílias apresentavam algum nível de consanguinidade; particularmente, oito desses casos apresentavam mutações em homozigose no gene COL7A1. Ainda assim, as formas autossômicas recessivas da doença eram a maioria mesmo nas famílias sem consanguinidade, com 41 famílias apresentando variantes em heterozigose composta (o que significa que o paciente recebeu variante deletéria diferente no mesmo gene de cada progenitor saudável). Como esperado para as formas autossômicas dominantes, houve maioria de seis casos de mutações de novo em heterozigose, não herdadas de nenhum dos pais; a transmissão vertical foi observada em apenas duas famílias, o que significa que a criança e seu pai ou mãe eram ambos afetados.A análise com microscopia eletrônica era o antigo método de referência para o diagnóstico de EB, mas seus altos custos e a dificuldade de acesso (poucos centros dispõem desse equipamento e talvez ainda menos pessoas tenham experiência em utilizá‐lo) determinaram gradativamente seu declínio.Como mencionado anteriormente, até recentemente o método de referência para o diagnóstico era o imunomapeamento em biopsia de pele. Embora geralmente ele consiga identificar o nível cutâneo onde ocorreu a clivagem com formação da bolha (intradérmica ou subepidérmica), não consegue indicar com certeza o gene afetado e, portanto, o padrão de herança de cada paciente. Além disso, é procedimento invasivo (com necessidade de anestesia local e posterior sutura) e os resultados não raramente são inconclusivos, sendo muitas vezes necessária uma segunda biopsia cutânea, o que pode ser particularmente problemático em pacientes com EB.Atualmente, a análise molecular tornou‐se ferramenta importante para diagnóstico mais preciso da EB. Não é novidade que seu uso tem sido fortemente recomendado não só por sua precisão e potencial menor custo, mas também porque evita danos à pele de pacientes tão vulneráveis, já que funciona bem com apenas uma gota de sangue ou até mesmo com pequena quantidade de saliva do paciente.Contudo, é importante apontar algumas desvantagens em relação ao diagnóstico genético da EB. Em primeiro lugar, métodos mais generalizados e recursos insuficientes destinados a testes moleculares, particularmente em regiões distantes. Além disso, há pelo menos 18 genes associados aos diversos tipos de EB, com mais de 1.000 mutações diferentes descritas; a abordagem anterior com sequenciamento de Sanger de um gene ou mesmo mutações específicas conhecidas pode não garantir a confirmação da etiologia, muitas vezes representando um caminho longo e mais caro para o diagnóstico.Felizmente, os avanços da técnica de NGS agora podem fornecer análises simultâneas de um ou de centenas de genes, não apenas com o mesmo custo, mas também de maneira muito mais rápida e automática. Além disso, existe a possibilidade de coleta de amostras de sangue em centros de atenção primária à saúde ou mesmo a utilização de kits que utilizam saliva que pode ser coletada em casa, e esses materiais podem ser simplesmente enviados por correio para unidades de referência, representando óbvia expansão do leque de testes.Aqui é importante ressaltar que o WES analisa não apenas genes relacionados à EB, mas na verdade todos os genes humanos. É claro que isso representa custo mais elevado para o teste quando comparado com um painel, mas ainda assim, na experiência dos autores, pode muitas vezes ser mais difícil para os laboratórios estabelecerem um painel de NGS direcionado menos dispendioso para uma única condição, em vez de oferecer WES para vários pacientes com várias hipóteses genéticas (desde deficiência intelectual até baixa estatura). Considerando tudo isso, embora o presente estudo tenha utilizado o WES para análise genética, acredita‐se que esses resultados possam ser aplicados a todas as técnicas de NGS, uma vez que mutações germinativas em genes relacionados à EB seriam detectadas pelo WES ou por um painel de NGS direcionado.Apesar de inicialmente ser considerado mais caro que o imunomapeamento, é importante ressaltar que os custos do NGS vêm caindo constantemente nos últimos anos. Aliás, o potencial custo‐efetividade do painel de NGS direcionado a genes relacionados à EB para diagnóstico em um país de dimensões continentais como o Brasil já foi sugerido por outro estudo recente.<a class="elsevierStyleCrossRef" href="#bib0095">7</a>Por fim, a aplicação potencial da terapia genética a uma doença rara e, até agora, incurável, como a EB, não pode ser prejudicada. Apesar dos inúmeros desafios nesse caminho, mais de uma pesquisa mostrou resultados promissores na utilização dessas novas abordagens terapêuticas<a class="elsevierStyleCrossRefs" href="#bib0105">9–11</a> em pacientes com diferentes tipos de EB. Como o conhecimento do genótipo é absolutamente necessário para esses casos selecionados, mais uma vez destaca‐se que o imunomapeamento por si só não forneceria informações suficientes para decidir se um determinado paciente é elegível ou não para um tratamento específico. Por último, considerando a crescente disponibilidade e procura de fertilização in vitro,<a class="elsevierStyleCrossRef" href="#bib0120">12</a> o diagnóstico genético da EB também se torna ainda mais necessário.ConclusãoA EB contempla um grupo de dermatoses genéticas caracterizadas por fragilidade grave e bolhas recorrentes. Por ser doença congênita rara causada por mutações em múltiplos genes, o diagnóstico adequado pode ser um desafio por uma série de razões.Embora o imunomapeamento tenha sido útil em serviços onde não há estudos moleculares disponíveis, a análise genética realizada por NGS mostrou maior taxa de diagnóstico. Além disso, todos os resultados positivos levarão à confirmação do padrão de herança de cada família, que muitas vezes o imunomapeamento não consegue prever. Além disso, em um futuro não tão distante, será necessário o conhecimento do genótipo para decidir se determinado paciente é elegível ou não para formas específicas de terapia gênica e também para técnicas de reprodução assistida.Por fim, conclui‐se que o estudo molecular (seja com painel de NGS direcionado ou WES) é custo‐efetivo para o diagnóstico de EB, não apenas por sua alta eficiência e precisão, mas também por dispensar a necessidade de biopsia de pele. Assim, considera‐se que proporcionará aos pacientes melhor avaliação do prognóstico geral, diagnóstico genético pré‐natal e aconselhamento genético.Suporte financeiroKim CA CNPQ 304897 / 2020‐5; FAPESP 2019 / 21644‐0.Matsumoto N – recebeu suporte da Japan Agency for Medical Research and Development (AMED) [números de concessão JP22ek0109486, JP22ek0109549, JP22ek0109493]; e Takeda Science Foundation.Contribuição dos autoresSamantha Vernaschi Kelmann: Contribuiu amplamente na concepção e planejamento do artigo, bem como na avaliação dermatológica e interpretação dos dados.Bruno de Oliveira Stephan: Contribuiu amplamente na concepção e planejamento do artigo, bem como na análise genética e interpretação dos dados.Silvia Maria de Macedo Barbosa: Contribuiu no seguimento clínico e manejo dos pacientes.Rita Tiziana Verardo Polastrini: Contribuiu no seguimento clínico e manejo dos pacientes.Zilda Najjar Prado de Oliveira: Contribuiu na execução e interpretação do imunomapeamento.Maria Cecília Rivitti‐Machado: Contribuiu na execução e interpretação do imunomapeamento.Gustavo Marquezani Spolador: Contribuiu no aconselhamento e manejo genético dos pacientes.Rachel Sayuri Honjo: Contribuiu na redação e revisão crítica do manuscrito.Ken Saida: Contribuiu para a execução e interpretação dos testes moleculares.Naomichi Matsumoto: Contribuiu na execução e interpretação dos testes moleculares.Chong Ae Kim: Contribuiu para a redação e revisão crítica do manuscrito.Conflito de interessesNenhum." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres2137110" "titulo" => "Resumo" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Fundamentos" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Limitações do estudo" ] 5 => array:2 [ "identificador" => "abst0030" "titulo" => "Conclusão" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1814630" "titulo" => "Palavras‐chave" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introdução" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Método" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Informações clínicas" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Mapeamento por imunofluorescência" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Análise molecular e classificação de variantes" ] ] ] 4 => array:3 [ "identificador" => "sec0030" "titulo" => "Resultados" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Achados clínicos" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Epidermólise bolhosa distrófica – COL7A1" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Epidermólise bolhosa simples – KRT5/KRT14/PLEC" ] 3 => array:2 [ "identificador" => "sec0050" "titulo" => "Epidermólise bolhosa juncional – COL17A1" ] 4 => array:2 [ "identificador" => "sec0055" "titulo" => "Achados genéticos" ] 5 => array:2 [ "identificador" => "sec0060" "titulo" => "Imunomapeamento" ] ] ] 5 => array:2 [ "identificador" => "sec0065" "titulo" => "Discussão" ] 6 => array:2 [ "identificador" => "sec0070" "titulo" => "Conclusão" ] 7 => array:2 [ "identificador" => "sec0075" "titulo" => "Suporte financeiro" ] 8 => array:2 [ "identificador" => "sec0080" "titulo" => "Contribuição dos autores" ] 9 => array:2 [ "identificador" => "sec0085" "titulo" => "Conflito de interesses" ] 10 => array:1 [ "titulo" => "Referências" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-04-14" "fechaAceptado" => "2023-07-21" "PalabrasClave" => array:1 [ "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras‐chave" "identificador" => "xpalclavsec1814630" "palabras" => array:3 [ 0 => "Epidermólise bolhosa" 1 => "Exoma" 2 => "Genética" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "pt" => array:3 [ "titulo" => "Resumo" "resumen" => "FundamentosA epidermólise bolhosa (EB) é caracterizada por fragilidade da pele e formação de bolhas. No Brasil, o diagnóstico geralmente é obtido por meio de imunomapeamento, que envolve a realização de biopsia de pele. Mais recentemente, o sequenciamento completo do exoma (WES, do inglês whole exoma sequencing) tornou‐se importante ferramenta para o diagnóstico dos subtipos de EB, fornecendo informações sobre o prognóstico, bem como possibilitando aconselhamento genético adequado às famílias. ObjetivoComparar os resultados do imunomapeamento e da análise molecular e descrever as características de uma coorte brasileira de pacientes com EB. MétodosOs pacientes foram submetidos à avaliação clínica e WES utilizando amostras de sangue periférico. Os resultados do WES foram comparados aos obtidos nos testes de imunomapeamento no tecido obtido por biopsia de pele. ResultadosForam classificados 67 pacientes de 60 famílias: 47 pacientes com EB distrófica (EBD) recessiva, quatro com EBD dominante, 15 com EB simples (EBS) e um com EB juncional (EBJ). As novas variantes causativas foram: 10/60 (16%) em COL7A1 associada a EBD recessiva e três outras variantes em EBD dominante; uma variante homozigótica em KRT5 e outra variante homozigótica em PLEC, ambas associadas à EBS. O imunomapeamento estava disponível para 59 dos 67 pacientes, e o resultado foi concordante com os resultados do exoma em 37 (62%), discordante em 13 (22%) e inconclusivo em nove pacientes (15%). Limitações do estudoEmbora a EB seja doença rara, para fins estatísticos, o número de pacientes avaliados por essa coorte ainda pode ser considerado limitado; por outro lado, houve diferença significante entre a proporção dos tipos de EB (apenas um caso com EBJ, contra mais de 50 com EBD), o que infelizmente representa viés de seleção. Além disso, para um pequeno subconjunto de famílias, a segregação (geralmente por meio do sequenciamento de Sanger) não era uma opção, seja em virtude do status de genitor(a) falecido(a) ou desconhecido(a) – principalmente o pai. ConclusãoEmbora o imunomapeamento tenha sido útil em serviços onde os estudos moleculares não estavam disponíveis, esse método invasivo pode fornecer diagnóstico errado ou resultado inconclusivo em cerca de 1/3 dos pacientes. Este estudo mostra que o WES é método eficaz para o diagnóstico e aconselhamento genético de pacientes com EB." "secciones" => array:6 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Fundamentos" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Limitações do estudo" ] 5 => array:2 [ "identificador" => "abst0030" "titulo" => "Conclusão" ] ] ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Como citar este artigo: Kelmann SV, Stephan BO, Barbosa SMM, Polastrini RTV, Oliveira ZNP, Rivitti‐Machado MC, et al. Advantages of whole‐exome sequencing over immunomapping in 67 Brazilian patients with epidermolysis bullosa. An Bras Dermatol. 2024;99:350–6." ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "Trabalho realizado em sua maior parte em São Paulo, SP, Brasil, no Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, onde o paciente frequentava a Unidade de Dor e Cuidados Paliativos Pediátricos e a Unidade de Genética; o imunomapeamento foi realizado pelo Departamento de Dermatologia da mesma instituição. Todos os testes genéticos foram realizados em colaboração com os colegas pesquisadores japoneses do Departamento de Genética Humana da Yokohama City University Graduate School of Medicine, Yokohama, Japão." ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<elsevierMultimedia ident="upi0005"></elsevierMultimedia>" "etiqueta" => "Appendix A" "titulo" => "Material suplementario" "identificador" => "sec0095" ] ] ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "tbl1" "etiqueta" => "Tabela 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Tabela " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Sequenciamento completo do exoma \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Imunomapeamento \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">59/59 pacientes confirmados (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">37/59 pacientes confirmados (62,7%) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3522969.png" ] ] ] ] "descripcion" => array:1 [ "pt" => "Comparação geral da confirmação diagnóstica por sequenciamento completo do exoma e imunomapeamento em pacientes com epidermólise bolhosa" ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Tabela 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Tabela " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AD, autossômica dominante; AR, autossômica recessiva; EBD, epidermólise bolhosa distrófica; EBJ, epidermólise bolhosa juncional; EBS, epidermólise bolhosa simples; ND, não disponível; WES, sequenciamento completo do exoma." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Família \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Paciente \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Etiologia genética (WES) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Imunomapeamento \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Correspondência \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inconclusivo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inconclusivo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Não realizado \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">27 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">27 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBJ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">39 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inconclusivo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inconclusivo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inconclusivo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inconclusivo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">39 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Não realizado \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">44 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD (sem especificação) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Não realizado \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">46 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Não realizado \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AR (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Não realizado \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">44 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">49 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">46 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">51 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD (COL7A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">52 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS AD (KRT5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">53 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS AD (KRT5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Não realizado \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">49 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">54 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS AR (KRT5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">55 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS AR (KRT5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">51 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">56 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS AD (KRT5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">52 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">57 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS AD (KRT5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inconclusivo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">53 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">58 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS AD (KRT14) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">59 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS AD (KRT14) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Não realizado \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">60 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS AD (KRT14) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Não realizado \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">54 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">61 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS AD (KRT14) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">55 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS AD (KRT14) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">56 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">63 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS AD (KRT14) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBD AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">57 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EB AR (PLEC) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">58 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">65 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS AD (PLEC) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inconclusivo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">59 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">66 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBS AR (PLEC) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inconclusivo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">60 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">67 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBJ (COL17A1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EBJ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3522970.png" ] ] ] ] "descripcion" => array:1 [ "pt" => "Comparação detalhada entre resultados de sequenciamento completo do exoma e imunomapeamento em pacientes com epidermólise bolhosa" ] ] 2 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.doc" "ficheroTamanyo" => 36391 ] ] ] "bibliografia" => array:2 [ "titulo" => "Referências" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:12 [ 0 => array:3 [ "identificador" => "bib0065" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Epidermolysis bullosa" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. 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Estatísticas

Artigo original

Vantagens do sequenciamento completo do exoma sobre o imunomapeamento em 67 pacientes brasileiros com epidermólise bolhosa

Samantha Vernaschi Kelmanna, Bruno de Oliveira Stephana,

Autor para correspondência

bruno.stephan@hc.fm.usp.br

Autor para correspondência.

, Silvia Maria de Macedo Barbosab, Rita Tiziana Verardo Polastrinib, Zilda Najjar Prado de Oliveirac, Maria Cecília Rivitti‐Machadoc, Gustavo Marquezani Spoladora, Rachel Sayuri Honjoa, Ken Saidad, Naomichi Matsumotod, Chong Ae Kima

a Unidade de Genética, Instituto da Criança, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil

b Unidade de Dor e Cuidados Paliativos, Instituto da Criança, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil

c Departamento de Dermatologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil

d Departamento de Genética Humana, Yokohama City University Graduate School of Medicine Yokohama, Yokohama, Japão

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            "correspondencia" => "Autor para correspond&#234;ncia&#46;"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Introdu&#231;&#227;o</span><p id="par0005" class="elsevierStylePara elsevierViewall">A epiderm&#243;lise bolhosa &#40;EB&#41; inclui um grupo de doen&#231;as gen&#233;ticas caracterizadas por fragilidade cut&#226;nea grave e bolhas recorrentes&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">1&#44;2</span></a> A maioria dos casos tem in&#237;cio logo ap&#243;s o nascimento ou na primeira inf&#226;ncia&#44; embora a idade de in&#237;cio das les&#245;es cut&#226;neas seja vari&#225;vel&#46; As les&#245;es cut&#226;neas geralmente ocorrem por trauma m&#237;nimo&#46; Como a membrana basal &#233; fr&#225;gil e facilmente danificada na EB&#44; h&#225; fluxo constante e posterior ac&#250;mulo de l&#237;quido extracelular na clivagem gerada entre epiderme e derme&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">No geral&#44; a EB compreende um grupo de doen&#231;as cong&#234;nitas raras causadas por variantes patog&#234;nicas em quase 20 genes relacionados &#224; express&#227;o de prote&#237;nas relacionadas &#224; ader&#234;ncia da pele&#44; especialmente aquelas localizadas na zona da membrana basal&#46; A preval&#234;ncia &#233; estimada em aproximadamente 8&#44;22&#58;1&#46;000&#46;000 e a incid&#234;ncia nos EUA &#233; considerada de 19&#44;6&#58;1&#46;000&#46;000 de rec&#233;m&#8208;nascidos&#44; com n&#250;meros semelhantes em outros pa&#237;ses e aparentemente sem grande distin&#231;&#227;o entre etnias&#46; Mais de 30 tipos diferentes de EB foram descritos&#44; com tentativa recente de dividi&#8208;los em quatro grandes grupos &#40;2020&#41;&#58; EB simples &#40;EBS&#41;&#44; EB distr&#243;fica &#40;EBD&#41;&#44; EB juncional &#40;EBJ&#41; e a forma h&#237;brida&#44; tamb&#233;m conhecida como s&#237;ndrome de Kindler &#40;EBK&#41;&#46; Tal classifica&#231;&#227;o &#233; baseada principalmente no padr&#227;o de heran&#231;a &#40;autoss&#244;mica dominante ou recessiva&#41;&#44; na gravidade do fen&#243;tipo e na an&#225;lise histopatol&#243;gica&#47;imunomapeamento&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">A an&#225;lise com microscopia eletr&#244;nica e&#44; posteriormente&#44; o imunomapeamento a partir de uma biopsia de pele&#44; eram o antigo m&#233;todo de refer&#234;ncia para o diagn&#243;stico de EB&#46; Embora ambos consigam identificar o n&#237;vel cut&#226;neo onde est&#225; situada a clivagem da bolha &#40;intrad&#233;rmica ou subepid&#233;rmica&#41; na maioria das vezes&#44; n&#227;o h&#225; indica&#231;&#227;o certeira do gene afetado e&#44; portanto&#44; do padr&#227;o de heran&#231;a de cada paciente&#46; Al&#233;m disso&#44; a biopsia de pele &#233; procedimento invasivo &#40;com necessidade de anestesia local e posterior sutura&#41;&#44; e quando seus resultados s&#227;o inconclusivos&#44; muitas vezes h&#225; atraso e necessidade de uma segunda amostra&#44; o que pode ser particularmente problem&#225;tico em pacientes com EB&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Nesse cen&#225;rio&#44; a an&#225;lise molecular tornou&#8208;se ferramenta importante para diagn&#243;stico mais preciso da EB&#44; especialmente dada a recente consolida&#231;&#227;o e o acesso mais f&#225;cil &#224;s t&#233;cnicas de sequenciamento de pr&#243;xima gera&#231;&#227;o &#40;NGS&#44; do ingl&#234;s <span class="elsevierStyleItalic">next generation sequencing</span>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">4&#8211;8</span></a> Aqui s&#227;o comparados os resultados do imunomapeamento e do WES de uma coorte brasileira de 67 pacientes com EB&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">M&#233;todo</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Informa&#231;&#245;es cl&#237;nicas</span><p id="par0025" class="elsevierStylePara elsevierViewall">Foram estudados 67 pacientes de 60 fam&#237;lias com diferentes tipos de EB&#44; todos atendidos na Unidade de Dor e Cuidados Paliativos Pedi&#225;tricos&#44; na Unidade de Gen&#233;tica do Instituto da Crian&#231;a e no Departamento de Dermatologia do Hospital das Cl&#237;nicas da Faculdade de Medicina da Universidade de S&#227;o Paulo&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Um protocolo cl&#237;nico foi elaborado considerando hist&#243;ria familiar&#44; exame f&#237;sico e dermatol&#243;gico&#44; evolu&#231;&#227;o cl&#237;nica e outros eventos cl&#237;nicos importantes&#46; Foram coletados o <span class="elsevierStyleItalic">pedigree</span> e feito o registro fotogr&#225;fico de todas as fam&#237;lias&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Mapeamento por imunofluoresc&#234;ncia</span><p id="par0035" class="elsevierStylePara elsevierViewall">O imunomapeamento consiste em t&#233;cnica de imunofluoresc&#234;ncia indireta aplicada em fragmento de pele contendo uma bolha totalmente preservada&#44; com an&#225;lise da presen&#231;a de ant&#237;genos na zona da membrana basal por meio da exposi&#231;&#227;o a anticorpos monoclonais fluorescentes&#46; Apenas para lembrar&#44; a imunofluoresc&#234;ncia direta &#233; restrita aos casos de EB autoimune adquirida &#40;que n&#227;o foram avaliados neste estudo&#41; e&#44; portanto&#44; in&#250;til para nossos pacientes com formas heredit&#225;rias de EB&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">A maioria dos pacientes j&#225; havia sido submetida ao imunomapeamento no laborat&#243;rio de Imunopatologia da institui&#231;&#227;o antes deste projeto&#46; Aqui&#44; os principais anticorpos utilizados foram anticorpo penfigoide bolhoso&#44; anticorpo laminina&#44; anticorpo col&#225;geno tipo IV e anticorpo col&#225;geno tipo VII&#46; Cada um desses anticorpos &#233; encontrado&#44; respectivamente&#44; nos seguintes locais da jun&#231;&#227;o dermoepid&#233;rmica&#58; hemidesmossomos&#44; l&#226;mina l&#250;cida&#44; l&#226;mina densa e subl&#226;mina densa&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Todas as an&#225;lises de imunomapeamento foram realizadas e revisadas pelo dermatologista chefe do laborat&#243;rio de Imunopatologia&#46; Por fim&#44; destaca&#8208;se o fato de que quatro fam&#237;lias foram inclu&#237;das nas etapas finais do estudo e&#44; portanto&#44; n&#227;o foram submetidas ao imunomapeamento&#59; al&#233;m disso&#44; havia quatro parentes de tr&#234;s fam&#237;lias nas quais os casos &#237;ndices j&#225; tinham resultados de imunomapeamento e moleculares dispon&#237;veis&#59; portanto&#44; para esses oito pacientes&#44; foi realizada apenas a confirma&#231;&#227;o molecular&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">An&#225;lise molecular e classifica&#231;&#227;o de variantes</span><p id="par0050" class="elsevierStylePara elsevierViewall">O sequenciamento completo do exoma &#40;WES&#44; do ingl&#234;s <span class="elsevierStyleItalic">whole&#8208;exome sequencing</span>&#41; foi realizado para todas as 60 fam&#237;lias&#59; amostras de sangue foram coletadas do probando e de seus pais&#44; mas a an&#225;lise preliminar concentrou&#8208;se principalmente no probando afetado&#46; Ap&#243;s a identifica&#231;&#227;o da&#40;s&#41; variante&#40;s&#41; candidata&#40;s&#41; no &#237;ndice&#44; a segrega&#231;&#227;o foi ent&#227;o realizada por sequenciamento de Sanger nos pais &#40;geralmente saud&#225;veis&#41;&#59; no caso de irm&#227;os afetados&#44; essa abordagem tamb&#233;m era realizada&#46; Todos os testes gen&#233;ticos foram realizados pelos parceiros investigadores japoneses em Yokohama&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">As variantes foram interpretadas e classificadas de acordo com as diretrizes de interpreta&#231;&#227;o de variantes do American College of Medical Genetics and Genomics &#40;ACMG&#59; 2015&#41;&#46; O caso somente foi considerado diagnosticado quando foram observadas variantes patog&#234;nicas ou provavelmente patog&#234;nicas em um gene associado ao fen&#243;tipo do indiv&#237;duo estudado&#44; com zigosidade compat&#237;vel e em padr&#227;o de heran&#231;a adequado&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Resultados</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Achados cl&#237;nicos</span><p id="par0060" class="elsevierStylePara elsevierViewall">Achados cl&#237;nicos t&#237;picos&#44; como bolhas difusas&#44; estavam presentes na maioria dos pacientes &#40;48 de 67&#41;&#46; Os sintomas e a idade de aparecimento eram obviamente vari&#225;veis&#44; mas a maioria apresentava les&#245;es cut&#226;neas t&#237;picas desde os primeiros dias de vida&#46; Como esperado para doen&#231;a autoss&#244;mica&#44; n&#227;o havia predom&#237;nio de g&#234;nero&#44; com 34 mulheres e 33 homens no presente grupo&#46; Al&#233;m disso&#44; ocorreram quatro &#243;bitos entre os casos de EBD recessiva&#44; todos com 20 anos ou menos&#44; falecidos por sepse seguida de fal&#234;ncia de m&#250;ltiplos &#243;rg&#227;os&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Epiderm&#243;lise bolhosa distr&#243;fica &#8211; COL7A1</span><p id="par0065" class="elsevierStylePara elsevierViewall">A grande maioria dos pacientes &#40;47&#47;67&#41; apresentava variantes no gene <span class="elsevierStyleItalic">COL7A1</span> associadas &#224; heran&#231;a autoss&#244;mica recessiva&#59; havia apenas tr&#234;s fam&#237;lias com recorr&#234;ncia e irm&#227;os afetados &#40;total de sete pacientes&#41;&#46; Dado que o diagn&#243;stico espec&#237;fico de EB foi sugerido em apenas 29 dos 46 pacientes submetidos ao imunomapeamento nesse subconjunto &#40;essa t&#233;cnica n&#227;o estava dispon&#237;vel para cinco indiv&#237;duos&#41;&#44; a concord&#226;ncia com o WES foi de 63&#37; para esse tipo de EB&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">De acordo com a literatura&#44; o fen&#243;tipo nesses casos tende a ser mais grave&#59; a maioria dos pacientes nasceu a termo com aparecimento de bolhas nos primeiros 2 dias de vida&#59; apenas dois deles nasceram sem unhas&#59; todos referiram prurido intenso&#44; e outros sintomas importantes eram comuns&#58; dor cr&#244;nica &#40;78&#37;&#41;&#44; desnutri&#231;&#227;o &#40;71&#44;5&#37;&#41;&#44; anemia &#40;48&#44;9&#37;&#41;&#44; estenose esof&#225;gica com necessidade de dilata&#231;&#227;o &#40;59&#44;6&#37;&#41; e atraso no desenvolvimento &#40;36&#37;&#41;&#46; Dentre eles&#44; tr&#234;s pacientes evolu&#237;ram com neoplasia maligna de c&#233;lulas escamosas&#44; dois deles na regi&#227;o do calc&#226;neo&#46; Como esperado&#44; as quatro mortes em todo o grupo foram de pacientes com EBD recessiva&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Por outro lado&#44; quatro dos pacientes com EBD apresentaram variantes no gene <span class="elsevierStyleItalic">COL7A1</span> associadas a padr&#227;o autoss&#244;mico dominante&#59; todos eram casos espor&#225;dicos em suas respectivas fam&#237;lias&#46; Em contraste com a forma recessiva&#44; os achados cl&#237;nicos aqui podem ser considerados geralmente leves&#58; as bolhas n&#227;o apareceram at&#233; aproximadamente 2 meses de vida e eram generalizadas em tr&#234;s pacientes&#44; enquanto confinadas &#224;s m&#227;os e p&#233;s &#40;forma acral&#41; em apenas um indiv&#237;duo&#59; havia perda parcial de unhas&#44; mas nenhum paciente apresentou pseudosindactilia&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Epiderm&#243;lise bolhosa simples &#8211; KRT5&#47;KRT14&#47;PLEC</span><p id="par0080" class="elsevierStylePara elsevierViewall">Apesar de ser o tipo mais comum de EB&#44; a EBS representou a minoria dos pacientes &#40;15 pacientes&#44; 12 fam&#237;lias&#41;&#46; Dos sete diferentes genes associados a essa forma da doen&#231;a&#44; foram identificadas muta&#231;&#245;es apenas nos genes <span class="elsevierStyleItalic">KRT5</span>&#44; <span class="elsevierStyleItalic">KRT14</span> e <span class="elsevierStyleItalic">PLEC</span>&#46; Considerando que o diagn&#243;stico espec&#237;fico de EBS foi indicado em apenas oito dos 12 pacientes submetidos ao imunomapeamento nesse grupo &#40;tr&#234;s indiv&#237;duos n&#227;o foram investigadas por essa t&#233;cnica&#44; pois eram familiares do caso &#237;ndice&#41;&#44; a concord&#226;ncia com o WES foi de quase 67&#37; para esse tipo de EB&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Dos seis pacientes com variantes do gene <span class="elsevierStyleItalic">KRT5</span>&#44; todos apresentaram bolhas nos primeiros 10 dias de vida&#44; principalmente nas extremidades&#44; acompanhadas de dor cr&#244;nica&#44; prurido e sudorese&#59; todos apresentavam algum grau de perda ungueal nos dedos das m&#227;os ou dos p&#233;s&#44; e um deles tamb&#233;m apresentava dentes fr&#225;geis&#44; mas nenhum deles apresentava estenose esof&#225;gica&#46; Havia quatro fam&#237;lias com a forma autoss&#244;mica dominante da doen&#231;a&#44; enquanto outras duas manifestaram padr&#227;o autoss&#244;mico recessivo&#46; Ainda assim&#44; n&#227;o houve diferen&#231;a cl&#237;nica significante entre os dois padr&#245;es de heran&#231;a&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Em rela&#231;&#227;o aos seis pacientes com variantes no gene <span class="elsevierStyleItalic">KRT14</span>&#44; todos tamb&#233;m apresentaram bolhas nos primeiros dias de vida e metade manifestou sudorese e anemia na primeira inf&#226;ncia&#44; mas curiosamente nenhum se queixou de prurido&#59; nenhum paciente apresentou pseudosindactilia ou milia&#46; Todos manifestaram padr&#227;o autoss&#244;mico dominante&#44; mas tr&#234;s eram da mesma fam&#237;lia &#40;pai e dois filhos de m&#227;es diferentes&#41;&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Por fim&#44; havia tr&#234;s pacientes com variantes do gene <span class="elsevierStyleItalic">PLEC</span>&#44; todos manifestando bolhas nas primeiras horas de vida&#46; As les&#245;es ocorreram principalmente nas extremidades&#44; com presen&#231;a de milia de pequeno grau&#44; mas os pacientes evolu&#237;ram com peso e estatura normais&#59; dois deles foram submetidos &#224; dilata&#231;&#227;o esof&#225;gica por estenose e um apresentou pseudosindactilia nos p&#233;s&#46; Todas essas fam&#237;lias manifestaram a forma autoss&#244;mica recessiva da doen&#231;a&#59; duas dessas fam&#237;lias apresentavam muta&#231;&#245;es em homozigose&#44; enquanto a restante apresentava variantes em heterozigose composta&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Epiderm&#243;lise bolhosa juncional &#8211; COL17A1</span><p id="par0100" class="elsevierStylePara elsevierViewall">O &#250;nico caso de EBJ foi uma menina com variantes homozigotas no gene <span class="elsevierStyleItalic">COL17A1</span>&#44; filha de pais consangu&#237;neos&#59; como o imunomapeamento desse caso isolado tamb&#233;m indicou EBJ&#44; a correspond&#234;ncia de ambas as t&#233;cnicas para essa forma da doen&#231;a foi de 100&#37; para esse tipo de EB&#46; O fen&#243;tipo da paciente poderia ser caracterizado como moderado&#59; ela apresentou bolhas desde o terceiro dia de vida e tamb&#233;m referia dores cr&#244;nicas e prurido constante&#46; Aos 16 anos&#44; a paciente apresentava dificuldade para caminhar&#44; acompanhada de anemia leve e desnutri&#231;&#227;o&#46; O exame dermatol&#243;gico revelou bolhas localizadas principalmente em &#225;reas com dobras &#40;bra&#231;os&#44; joelhos&#44; p&#233;s&#41;&#44; sem milia&#44; e os cabelos eram finos e fr&#225;geis&#59; notavelmente&#44; as unhas dos dedos dos p&#233;s estavam ausentes&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Achados gen&#233;ticos</span><p id="par0105" class="elsevierStylePara elsevierViewall">Foram estudados 67 pacientes de 60 fam&#237;lias com diferentes tipos de EB&#44; todos atendidos no hospital da institui&#231;&#227;o&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Nesse cen&#225;rio&#44; havia 47 pacientes &#40;43 fam&#237;lias&#41; com EB recessiva&#44; quatro pacientes com EB dominante&#44; 15 pacientes &#40;12 fam&#237;lias&#41; com EBS e uma paciente com EBJ&#46; Das 60 variantes diferentes em genes relacionados &#224; EB observadas nos pacientes&#44; 15 nunca foram publicadas na literatura&#44; que seja de conhecimento dos autores&#58; dez associadas &#224; EBD recessiva&#44; tr&#234;s &#224; EBD dominante e duas &#224; EBS&#46; A maioria delas era de muta&#231;&#245;es nulas &#40;variantes <span class="elsevierStyleItalic">nonsense</span>&#44; <span class="elsevierStyleItalic">frameshift</span> ou site de <span class="elsevierStyleItalic">splice</span> can&#244;nico&#41;&#44; com apenas tr&#234;s variantes <span class="elsevierStyleItalic">missense</span>&#46; Os detalhes est&#227;o descritos nos materiais suplementares&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Imunomapeamento</span><p id="par0115" class="elsevierStylePara elsevierViewall">O imunomapeamento estava dispon&#237;vel em 59 desses pacientes&#59; oito do total de 67 pacientes n&#227;o puderam prosseguir para investiga&#231;&#227;o com biopsia de pele&#46; Houve concord&#226;ncia entre os resultados do imunomapeamento e do exoma em 37 &#40;62&#37;&#41; desses casos&#44; enquanto em 13 &#40;22&#37;&#41; foi provado que o imunomapeamento estava errado pela an&#225;lise molecular&#46; Al&#233;m disso&#44; houve nove pacientes &#40;15&#37;&#41; nos quais os resultados do imunomapeamento foram inconclusivos&#44; como mostrado nas <a class="elsevierStyleCrossRefs" href="#tbl1">tabelas 1 e 2</a>&#46; Portanto&#44; de um total de 22 pacientes&#44; o imunomapeamento estabeleceu diagn&#243;stico errado ou nenhum diagn&#243;stico em 37&#37;&#46;</p><elsevierMultimedia ident="tbl1"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">Por fim&#44; foi realizada a an&#225;lise de concord&#226;ncia quantificada em rela&#231;&#227;o ao imunomapeamento dos 50 pacientes que receberam resultados positivos &#40;38&#41; ou negativos &#40;12&#41;&#44; quando comparados com os resultados do WES&#46; Embora o teste Kappa tenda a subestimar o n&#237;vel de concord&#226;ncia em rela&#231;&#227;o a doen&#231;as raras&#44; nesse caso ele foi igual a<span class="elsevierStyleHsp" style=""></span>&#8722;<span class="elsevierStyleHsp" style=""></span>0&#44;261 &#40;intervalo de confian&#231;a de 95&#37; de<span class="elsevierStyleHsp" style=""></span>&#8722;<span class="elsevierStyleHsp" style=""></span>0&#44;388 a<span class="elsevierStyleHsp" style=""></span>&#8722;<span class="elsevierStyleHsp" style=""></span>0&#44;135&#41;&#44; indicando n&#227;o haver concord&#226;ncia entre esses dois exames&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Discuss&#227;o</span><p id="par0125" class="elsevierStylePara elsevierViewall">Houve claro predom&#237;nio de EBD &#40;associada &#224; muta&#231;&#227;o no gene <span class="elsevierStyleItalic">COL7A1</span>&#41;&#44; com 51 dos 67 pacientes &#40;76&#37;&#41; apresentando esse tipo de doen&#231;a&#44; que geralmente representa fen&#243;tipo mais grave&#44; principalmente na forma autoss&#244;mica recessiva&#46; Considerando que os pacientes deste estudo frequentavam o grupo de Dor e Cuidados Paliativos&#44; j&#225; era esperada elevada frequ&#234;ncia de gravidade&#59; ainda assim&#44; a contagem total de mortes em pacientes com menos de 20 anos se destaca das taxas de mortalidade brasileiras e globais relatadas&#44; talvez indicando a falta de apoio adequado e intenso ao cuidado desses pacientes em alguns hospitais locais&#46; Fora isso&#44; os fen&#243;tipos foram semelhantes aos descritos na literatura para cada respectivo gene&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Em rela&#231;&#227;o &#224; hist&#243;ria familiar&#44; &#233; importante ressaltar que ela mostrou certo vi&#233;s&#44; visto que 11 das 60 fam&#237;lias apresentavam algum n&#237;vel de consanguinidade&#59; particularmente&#44; oito desses casos apresentavam muta&#231;&#245;es em homozigose no gene <span class="elsevierStyleItalic">COL7A1</span>&#46; Ainda assim&#44; as formas autoss&#244;micas recessivas da doen&#231;a eram a maioria mesmo nas fam&#237;lias sem consanguinidade&#44; com 41 fam&#237;lias apresentando variantes em heterozigose composta &#40;o que significa que o paciente recebeu variante delet&#233;ria diferente no mesmo gene de cada progenitor saud&#225;vel&#41;&#46; Como esperado para as formas autoss&#244;micas dominantes&#44; houve maioria de seis casos de muta&#231;&#245;es <span class="elsevierStyleItalic">de novo</span> em heterozigose&#44; n&#227;o herdadas de nenhum dos pais&#59; a transmiss&#227;o vertical foi observada em apenas duas fam&#237;lias&#44; o que significa que a crian&#231;a e seu pai ou m&#227;e eram ambos afetados&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">A an&#225;lise com microscopia eletr&#244;nica era o antigo m&#233;todo de refer&#234;ncia para o diagn&#243;stico de EB&#44; mas seus altos custos e a dificuldade de acesso &#40;poucos centros disp&#245;em desse equipamento e talvez ainda menos pessoas tenham experi&#234;ncia em utiliz&#225;&#8208;lo&#41; determinaram gradativamente seu decl&#237;nio&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Como mencionado anteriormente&#44; at&#233; recentemente o m&#233;todo de refer&#234;ncia para o diagn&#243;stico era o imunomapeamento em biopsia de pele&#46; Embora geralmente ele consiga identificar o n&#237;vel cut&#226;neo onde ocorreu a clivagem com forma&#231;&#227;o da bolha &#40;intrad&#233;rmica ou subepid&#233;rmica&#41;&#44; n&#227;o consegue indicar com certeza o gene afetado e&#44; portanto&#44; o padr&#227;o de heran&#231;a de cada paciente&#46; Al&#233;m disso&#44; &#233; procedimento invasivo &#40;com necessidade de anestesia local e posterior sutura&#41; e os resultados n&#227;o raramente s&#227;o inconclusivos&#44; sendo muitas vezes necess&#225;ria uma segunda biopsia cut&#226;nea&#44; o que pode ser particularmente problem&#225;tico em pacientes com EB&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Atualmente&#44; a an&#225;lise molecular tornou&#8208;se ferramenta importante para diagn&#243;stico mais preciso da EB&#46; N&#227;o &#233; novidade que seu uso tem sido fortemente recomendado n&#227;o s&#243; por sua precis&#227;o e potencial menor custo&#44; mas tamb&#233;m porque evita danos &#224; pele de pacientes t&#227;o vulner&#225;veis&#44; j&#225; que funciona bem com apenas uma gota de sangue ou at&#233; mesmo com pequena quantidade de saliva do paciente&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Contudo&#44; &#233; importante apontar algumas desvantagens em rela&#231;&#227;o ao diagn&#243;stico gen&#233;tico da EB&#46; Em primeiro lugar&#44; m&#233;todos mais generalizados e recursos insuficientes destinados a testes moleculares&#44; particularmente em regi&#245;es distantes&#46; Al&#233;m disso&#44; h&#225; pelo menos 18 genes associados aos diversos tipos de EB&#44; com mais de 1&#46;000 muta&#231;&#245;es diferentes descritas&#59; a abordagem anterior com sequenciamento de Sanger de um gene ou mesmo muta&#231;&#245;es espec&#237;ficas conhecidas pode n&#227;o garantir a confirma&#231;&#227;o da etiologia&#44; muitas vezes representando um caminho longo e mais caro para o diagn&#243;stico&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Felizmente&#44; os avan&#231;os da t&#233;cnica de NGS agora podem fornecer an&#225;lises simult&#226;neas de um ou de centenas de genes&#44; n&#227;o apenas com o mesmo custo&#44; mas tamb&#233;m de maneira muito mais r&#225;pida e autom&#225;tica&#46; Al&#233;m disso&#44; existe a possibilidade de coleta de amostras de sangue em centros de aten&#231;&#227;o prim&#225;ria &#224; sa&#250;de ou mesmo a utiliza&#231;&#227;o de <span class="elsevierStyleItalic">kits</span> que utilizam saliva que pode ser coletada em casa&#44; e esses materiais podem ser simplesmente enviados por correio para unidades de refer&#234;ncia&#44; representando &#243;bvia expans&#227;o do leque de testes&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Aqui &#233; importante ressaltar que o WES analisa n&#227;o apenas genes relacionados &#224; EB&#44; mas na verdade todos os genes humanos&#46; &#201; claro que isso representa custo mais elevado para o teste quando comparado com um painel&#44; mas ainda assim&#44; na experi&#234;ncia dos autores&#44; pode muitas vezes ser mais dif&#237;cil para os laborat&#243;rios estabelecerem um painel de NGS direcionado menos dispendioso para uma &#250;nica condi&#231;&#227;o&#44; em vez de oferecer WES para v&#225;rios pacientes com v&#225;rias hip&#243;teses gen&#233;ticas &#40;desde defici&#234;ncia intelectual at&#233; baixa estatura&#41;&#46; Considerando tudo isso&#44; embora o presente estudo tenha utilizado o WES para an&#225;lise gen&#233;tica&#44; acredita&#8208;se que esses resultados possam ser aplicados a todas as t&#233;cnicas de NGS&#44; uma vez que muta&#231;&#245;es germinativas em genes relacionados &#224; EB seriam detectadas pelo WES ou por um painel de NGS direcionado&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Apesar de inicialmente ser considerado mais caro que o imunomapeamento&#44; &#233; importante ressaltar que os custos do NGS v&#234;m caindo constantemente nos &#250;ltimos anos&#46; Ali&#225;s&#44; o potencial custo&#8208;efetividade do painel de NGS direcionado a genes relacionados &#224; EB para diagn&#243;stico em um pa&#237;s de dimens&#245;es continentais como o Brasil j&#225; foi sugerido por outro estudo recente&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">7</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Por fim&#44; a aplica&#231;&#227;o potencial da terapia gen&#233;tica a uma doen&#231;a rara e&#44; at&#233; agora&#44; incur&#225;vel&#44; como a EB&#44; n&#227;o pode ser prejudicada&#46; Apesar dos in&#250;meros desafios nesse caminho&#44; mais de uma pesquisa mostrou resultados promissores na utiliza&#231;&#227;o dessas novas abordagens terap&#234;uticas<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">9&#8211;11</span></a> em pacientes com diferentes tipos de EB&#46; Como o conhecimento do gen&#243;tipo &#233; absolutamente necess&#225;rio para esses casos selecionados&#44; mais uma vez destaca&#8208;se que o imunomapeamento por si s&#243; n&#227;o forneceria informa&#231;&#245;es suficientes para decidir se um determinado paciente &#233; eleg&#237;vel ou n&#227;o para um tratamento espec&#237;fico&#46; Por &#250;ltimo&#44; considerando a crescente disponibilidade e procura de fertiliza&#231;&#227;o <span class="elsevierStyleItalic">in vitro</span>&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">12</span></a> o diagn&#243;stico gen&#233;tico da EB tamb&#233;m se torna ainda mais necess&#225;rio&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conclus&#227;o</span><p id="par0175" class="elsevierStylePara elsevierViewall">A EB contempla um grupo de dermatoses gen&#233;ticas caracterizadas por fragilidade grave e bolhas recorrentes&#46; Por ser doen&#231;a cong&#234;nita rara causada por muta&#231;&#245;es em m&#250;ltiplos genes&#44; o diagn&#243;stico adequado pode ser um desafio por uma s&#233;rie de raz&#245;es&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Embora o imunomapeamento tenha sido &#250;til em servi&#231;os onde n&#227;o h&#225; estudos moleculares dispon&#237;veis&#44; a an&#225;lise gen&#233;tica realizada por NGS mostrou maior taxa de diagn&#243;stico&#46; Al&#233;m disso&#44; todos os resultados positivos levar&#227;o &#224; confirma&#231;&#227;o do padr&#227;o de heran&#231;a de cada fam&#237;lia&#44; que muitas vezes o imunomapeamento n&#227;o consegue prever&#46; Al&#233;m disso&#44; em um futuro n&#227;o t&#227;o distante&#44; ser&#225; necess&#225;rio o conhecimento do gen&#243;tipo para decidir se determinado paciente &#233; eleg&#237;vel ou n&#227;o para formas espec&#237;ficas de terapia g&#234;nica e tamb&#233;m para t&#233;cnicas de reprodu&#231;&#227;o assistida&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Por fim&#44; conclui&#8208;se que o estudo molecular &#40;seja com painel de NGS direcionado ou WES&#41; &#233; custo&#8208;efetivo para o diagn&#243;stico de EB&#44; n&#227;o apenas por sua alta efici&#234;ncia e precis&#227;o&#44; mas tamb&#233;m por dispensar a necessidade de biopsia de pele&#46; Assim&#44; considera&#8208;se que proporcionar&#225; aos pacientes melhor avalia&#231;&#227;o do progn&#243;stico geral&#44; diagn&#243;stico gen&#233;tico pr&#233;&#8208;natal e aconselhamento gen&#233;tico&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Suporte financeiro</span><p id="par0190" class="elsevierStylePara elsevierViewall">Kim CA CNPQ 304897 &#47; 2020&#8208;5&#59; FAPESP 2019 &#47; 21644&#8208;0&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Matsumoto N &#8211; recebeu suporte da Japan Agency for Medical Research and Development &#40;AMED&#41; &#91;n&#250;meros de concess&#227;o JP22ek0109486&#44; JP22ek0109549&#44; JP22ek0109493&#93;&#59; e Takeda Science Foundation&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Contribui&#231;&#227;o dos autores</span><p id="par0200" class="elsevierStylePara elsevierViewall">Samantha Vernaschi Kelmann&#58; Contribuiu amplamente na concep&#231;&#227;o e planejamento do artigo&#44; bem como na avalia&#231;&#227;o dermatol&#243;gica e interpreta&#231;&#227;o dos dados&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">Bruno de Oliveira Stephan&#58; Contribuiu amplamente na concep&#231;&#227;o e planejamento do artigo&#44; bem como na an&#225;lise gen&#233;tica e interpreta&#231;&#227;o dos dados&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Silvia Maria de Macedo Barbosa&#58; Contribuiu no seguimento cl&#237;nico e manejo dos pacientes&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">Rita Tiziana Verardo Polastrini&#58; Contribuiu no seguimento cl&#237;nico e manejo dos pacientes&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Zilda Najjar Prado de Oliveira&#58; Contribuiu na execu&#231;&#227;o e interpreta&#231;&#227;o do imunomapeamento&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Maria Cec&#237;lia Rivitti&#8208;Machado&#58; Contribuiu na execu&#231;&#227;o e interpreta&#231;&#227;o do imunomapeamento&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Gustavo Marquezani Spolador&#58; Contribuiu no aconselhamento e manejo gen&#233;tico dos pacientes&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">Rachel Sayuri Honjo&#58; Contribuiu na reda&#231;&#227;o e revis&#227;o cr&#237;tica do manuscrito&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Ken Saida&#58; Contribuiu para a execu&#231;&#227;o e interpreta&#231;&#227;o dos testes moleculares&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">Naomichi Matsumoto&#58; Contribuiu na execu&#231;&#227;o e interpreta&#231;&#227;o dos testes moleculares&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Chong Ae Kim&#58; Contribuiu para a reda&#231;&#227;o e revis&#227;o cr&#237;tica do manuscrito&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflito de interesses</span><p id="par0255" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Fundamentos</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A epiderm&#243;lise bolhosa &#40;EB&#41; &#233; caracterizada por fragilidade da pele e forma&#231;&#227;o de bolhas&#46; No Brasil&#44; o diagn&#243;stico geralmente &#233; obtido por meio de imunomapeamento&#44; que envolve a realiza&#231;&#227;o de biopsia de pele&#46; Mais recentemente&#44; o sequenciamento completo do exoma &#40;WES&#44; do ingl&#234;s <span class="elsevierStyleItalic">whole exoma sequencing</span>&#41; tornou&#8208;se importante ferramenta para o diagn&#243;stico dos subtipos de EB&#44; fornecendo informa&#231;&#245;es sobre o progn&#243;stico&#44; bem como possibilitando aconselhamento gen&#233;tico adequado &#224;s fam&#237;lias&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objetivo</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Comparar os resultados do imunomapeamento e da an&#225;lise molecular e descrever as caracter&#237;sticas de uma coorte brasileira de pacientes com EB&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">M&#233;todos</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Os pacientes foram submetidos &#224; avalia&#231;&#227;o cl&#237;nica e WES utilizando amostras de sangue perif&#233;rico&#46; Os resultados do WES foram comparados aos obtidos nos testes de imunomapeamento no tecido obtido por biopsia de pele&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Resultados</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Foram classificados 67 pacientes de 60 fam&#237;lias&#58; 47 pacientes com EB distr&#243;fica &#40;EBD&#41; recessiva&#44; quatro com EBD dominante&#44; 15 com EB simples &#40;EBS&#41; e um com EB juncional &#40;EBJ&#41;&#46; As novas variantes causativas foram&#58; 10&#47;60 &#40;16&#37;&#41; em COL7A1 associada a EBD recessiva e tr&#234;s outras variantes em EBD dominante&#59; uma variante homozig&#243;tica em KRT5 e outra variante homozig&#243;tica em PLEC&#44; ambas associadas &#224; EBS&#46; O imunomapeamento estava dispon&#237;vel para 59 dos 67 pacientes&#44; e o resultado foi concordante com os resultados do exoma em 37 &#40;62&#37;&#41;&#44; discordante em 13 &#40;22&#37;&#41; e inconclusivo em nove pacientes &#40;15&#37;&#41;&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Limita&#231;&#245;es do estudo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Embora a EB seja doen&#231;a rara&#44; para fins estat&#237;sticos&#44; o n&#250;mero de pacientes avaliados por essa coorte ainda pode ser considerado limitado&#59; por outro lado&#44; houve diferen&#231;a significante entre a propor&#231;&#227;o dos tipos de EB &#40;apenas um caso com EBJ&#44; contra mais de 50 com EBD&#41;&#44; o que infelizmente representa vi&#233;s de sele&#231;&#227;o&#46; Al&#233;m disso&#44; para um pequeno subconjunto de fam&#237;lias&#44; a segrega&#231;&#227;o &#40;geralmente por meio do sequenciamento de Sanger&#41; n&#227;o era uma op&#231;&#227;o&#44; seja em virtude do <span class="elsevierStyleItalic">status</span> de genitor&#40;a&#41; falecido&#40;a&#41; ou desconhecido&#40;a&#41; &#8211; principalmente o pai&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclus&#227;o</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Embora o imunomapeamento tenha sido &#250;til em servi&#231;os onde os estudos moleculares n&#227;o estavam dispon&#237;veis&#44; esse m&#233;todo invasivo pode fornecer diagn&#243;stico errado ou resultado inconclusivo em cerca de 1&#47;3 dos pacientes&#46; Este estudo mostra que o WES &#233; m&#233;todo eficaz para o diagn&#243;stico e aconselhamento gen&#233;tico de pacientes com EB&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Como citar este artigo&#58; Kelmann SV&#44; Stephan BO&#44; Barbosa SMM&#44; Polastrini RTV&#44; Oliveira ZNP&#44; Rivitti&#8208;Machado MC&#44; et al&#46; Advantages of whole&#8208;exome sequencing over immunomapping in 67 Brazilian patients with epidermolysis bullosa&#46; An Bras Dermatol&#46; 2024&#59;99&#58;350&#8211;6&#46;</p>"
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                  \t\t\t\t" scope="col">Sequenciamento completo do exoma&nbsp;\t\t\t\t\t\t\n
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">AD&#44; autoss&#244;mica dominante&#59; AR&#44; autoss&#244;mica recessiva&#59; EBD&#44; epiderm&#243;lise bolhosa distr&#243;fica&#59; EBJ&#44; epiderm&#243;lise bolhosa juncional&#59; EBS&#44; epiderm&#243;lise bolhosa simples&#59; ND&#44; n&#227;o dispon&#237;vel&#59; WES&#44; sequenciamento completo do exoma&#46;</p>"
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                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Inconclusivo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inconclusivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o realizado&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">EBD AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">EBD AR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">EBD AR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">EBD AR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">25&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR &#40;C<span class="elsevierStyleItalic">OL</span>7A1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">EBD AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBJ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inconclusivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inconclusivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inconclusivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inconclusivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o realizado&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD &#40;sem especifica&#231;&#227;o&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o realizado&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o realizado&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AR &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o realizado&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AD &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AD &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AD &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AD &#40;<span class="elsevierStyleItalic">COL7A1</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBD AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBS AD &#40;<span class="elsevierStyleItalic">KRT5</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBS AD &#40;<span class="elsevierStyleItalic">KRT5</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o realizado&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">54&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBS AR &#40;<span class="elsevierStyleItalic">KRT5</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  """
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        "descripcion" => array:1 [
          "pt" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Compara&#231;&#227;o detalhada entre resultados de sequenciamento completo do exoma e imunomapeamento em pacientes com epiderm&#243;lise bolhosa</p>"
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          "fichero" => "mmc1.doc"
          "ficheroTamanyo" => 36391
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    "bibliografia" => array:2 [
      "titulo" => "Refer&#234;ncias"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:12 [
            0 => array:3 [
              "identificador" => "bib0065"
              "etiqueta" => "1"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Epidermolysis bullosa"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Bardhan"
                            1 => "L&#46; Bruckner-Tuderman"
                            2 => "I&#46;L&#46;C&#46; Chapple"
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Informação do artigo

ISSN: 26662752
Idioma original: Português

DOI:10.1016/j.abdp.2024.02.005

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