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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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                  \t\t\t\t" scope="col">Sequenciamento completo do exoma&nbsp;\t\t\t\t\t\t\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></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</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
                  \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</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</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
                  \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  " 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">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">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
                  \t\t\t\t\ttable-entry\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
                  \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">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\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
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                  \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
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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
                  \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
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \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">40&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
                  \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
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                  \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
                  \t\t\t\t\ttop\n
                  \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
                  \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-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&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">55&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
                  \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
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">EBD AD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">EB AR &#40;<span class="elsevierStyleItalic">PLEC</span>&#41;&nbsp;\t\t\t\t\t\t\n
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                  \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
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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
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                  \t\t\t\t">58&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
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                  \t\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">EBS AD &#40;<span class="elsevierStyleItalic">PLEC</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
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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
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">EBS AR &#40;<span class="elsevierStyleItalic">PLEC</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
                  \t\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
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&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">EBJ &#40;<span class="elsevierStyleItalic">COL17A1</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">EBJ&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">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "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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                            0 => "A&#46; Bardhan"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32973163"
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                      "doi" => "10.1111/bjd.18921"
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                        "tituloSerie" => "Br J Dermatol&#46;"
                        "fecha" => "2020"
                        "volumen" => "183"
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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,
Corresponding author
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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    "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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              "titulo" => "Epiderm&#243;lise bolhosa simples &#8211; KRT5&#47;KRT14&#47;PLEC"
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            0 => "Epiderm&#243;lise bolhosa"
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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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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Trabalho realizado em sua maior parte em S&#227;o Paulo&#44; SP&#44; Brasil&#44; no Instituto da Crian&#231;a do Hospital das Cl&#237;nicas da Faculdade de Medicina da Universidade de S&#227;o Paulo&#44; onde o paciente frequentava a Unidade de Dor e Cuidados Paliativos Pedi&#225;tricos e a Unidade de Gen&#233;tica&#59; o imunomapeamento foi realizado pelo Departamento de Dermatologia da mesma institui&#231;&#227;o&#46; Todos os testes gen&#233;ticos foram realizados em colabora&#231;&#227;o com os colegas pesquisadores japoneses do Departamento de Gen&#233;tica Humana da Yokohama City University Graduate School of Medicine&#44; Yokohama&#44; Jap&#227;o&#46;</p>"
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                  \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&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" scope="col">Imunomapeamento&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">59&#47;59 pacientes confirmados &#40;100&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">37&#47;59 pacientes confirmados &#40;62&#44;7&#37;&#41;&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\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Fam&#237;lia&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">EBD AR&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">EBD AR&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  " align="left" valign="\n
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                  \t\t\t\t">EBD AR&nbsp;\t\t\t\t\t\t\n
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                  \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
                  \t\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&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">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">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
                  \t\t\t\t  " align="left" valign="\n
                  \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
                  \t\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&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
                  \t\t\t\t\ttop\n
                  \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
                  \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-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&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">55&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
                  \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-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&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">56&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-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&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">57&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">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">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">58&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">KRT14</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
                  \t\t\t\t\ttop\n
                  \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">59&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">KRT14</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" 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">&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">60&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">KRT14</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">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">61&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">KRT14</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-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&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">62&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">EBS AD &#40;<span class="elsevierStyleItalic">KRT14</span>&#41;&nbsp;\t\t\t\t\t\t\n
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Article information
ISSN: 26662752
Original language: Portuguese
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