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CNVs em loci de suscetibilidade com penetrância incompleta: da certeza no diagnóstico à incerteza no prognóstico
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Advisor(s)
Abstract(s)
O teste genético de array é a primeira linha no diagnóstico genético pós-
-natal de situações como défice cognitivo, autismo e anomalias congénitas.
Em pré-natal, este teste está indicado em gravidezes com
anomalias ecográficas. Comparativamente ao cariotipo possibilita um
aumento no diagnóstico entre 10-20% em pós-natal e 5-10% em prénatal.
No entanto, também identifica alterações associadas a fenótipos
variáveis, com penetrância incompleta (CNVs-LS), conferindo aumento
da suscetibilidade a doenças do neuro-desenvolvimento, mas com
prognóstico incer to. Neste estudo pretendemos definir um conjunto
de CNVs-LS e a sua penetrância, estimada com dados da literatura,
aferindo a sua ocorrência na coor te com teste genético de array realizado
no INSA-DG-UCI. Definiram-se 21 CNVs-LS e dum total de 835 diagnósticos
em pós-natal e 317 em pré-natal, identificaram-se 36 casos
pós-natal e 11 em pré-natal, correspondendo a 4,3% e 3,5% do total,
respetivamente. A penetrância estimada para as CNVs-LS apresenta
variabilidade inter-publicações, e inter-fenótipo na população estudada,
embora seja concordante para algumas variantes. Aferir a penetrância
por variante é uma tarefa complexa e a análise por teste genético
de array acarreta ainda incer tezas no diagnóstico e aconselhamento
genético, dificuldades apenas superadas com o decorrer do tempo,
estudo de mais coor tes e conhecimento das interações genótipo-
-ambiente-fenótipo.
developmental delay, autism spectrum disorders, and congenital abnormalities in postnatal diagnosis and for ultrasound abnormalities in prenatal diagnosis. CMA when compared to kar yotype can increase the detection of variants with clinical significance up to 10-20% in postnatal diagnosis and up to 5-18% in prenatal diagnosis. Never theless CMA also detects incomplete penetrance neuro-susceptibility loci variants (CNV-SL), with clinical significance but uncer tain outcome. The aim of this study is to identif y from the literature a set of CNV-SL, and the corresponding penetrance, determining the occurrence in the cohor t from INSA-DG-UCI. From a total number of 835 postnatal samples and 317 prenatal samples we have identified 36 and 11 cases, respectively, with a variant in the 21 CNV-SL set obtained from the literature. The estimated penetrance presents some inter-publication variability, especially when concerning samples with dif ferent phenotypes, with some variants showing concordance, never theless. Estimating penetrance for CNV-SL is a complex task and clarif ying uncer tainty in these cases is still far from being accomplished. Only time, analysis of larger cohor ts, and future knowledge of genotype- -environment-phenotype interactions will overcome this dif ficulty allowing to improve the estimation of clinical impact for the subject or carriers in the family.
developmental delay, autism spectrum disorders, and congenital abnormalities in postnatal diagnosis and for ultrasound abnormalities in prenatal diagnosis. CMA when compared to kar yotype can increase the detection of variants with clinical significance up to 10-20% in postnatal diagnosis and up to 5-18% in prenatal diagnosis. Never theless CMA also detects incomplete penetrance neuro-susceptibility loci variants (CNV-SL), with clinical significance but uncer tain outcome. The aim of this study is to identif y from the literature a set of CNV-SL, and the corresponding penetrance, determining the occurrence in the cohor t from INSA-DG-UCI. From a total number of 835 postnatal samples and 317 prenatal samples we have identified 36 and 11 cases, respectively, with a variant in the 21 CNV-SL set obtained from the literature. The estimated penetrance presents some inter-publication variability, especially when concerning samples with dif ferent phenotypes, with some variants showing concordance, never theless. Estimating penetrance for CNV-SL is a complex task and clarif ying uncer tainty in these cases is still far from being accomplished. Only time, analysis of larger cohor ts, and future knowledge of genotype- -environment-phenotype interactions will overcome this dif ficulty allowing to improve the estimation of clinical impact for the subject or carriers in the family.
Description
Keywords
Anomalias Cromossómicas Copy Number Variants – CNVs Teste Genético de Array Diagnóstico Genético Diagnóstico Pré-natal Diagnóstico Pós-natal Doenças Genéticas
Pedagogical Context
Citation
Boletim Epidemiológico Observações. 2018 setembro-dezembro;7(23):57-61
Publisher
Instituto Nacional de Saúde Doutor Ricardo Jorge, IP