RESUMO
BACKGROUND: Array-comparative genomic hybridization (array-CGH) is a widely used technique to detect copy number variants (CNVs) associated with developmental delay/intellectual disability (DD/ID). AIMS: Identification of genomic disorders in DD/ID. MATERIALS AND METHODS: We performed a comprehensive array-CGH investigation of 1,015 consecutive cases with DD/ID and combined literature mining, genetic evidence, evolutionary constraint scores, and functional information in order to assess the pathogenicity of the CNVs. RESULTS: We identified non-benign CNVs in 29% of patients. Amongst the pathogenic variants (11%), detected with a yield consistent with the literature, we found rare genomic disorders and CNVs spanning known disease genes. We further identified and discussed 51 cases with likely pathogenic CNVs spanning novel candidate genes, including genes encoding synaptic components and/or proteins involved in corticogenesis. Additionally, we identified two deletions spanning potential Topological Associated Domain (TAD) boundaries probably affecting the regulatory landscape. DISCUSSION AND CONCLUSION: We show how phenotypic and genetic analyses of array-CGH data allow unraveling complex cases, identifying rare disease genes, and revealing unexpected position effects.
Assuntos
Variações do Número de Cópias de DNA/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Adolescente , Adulto , Criança , Pré-Escolar , Efeitos da Posição Cromossômica/genética , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/patologia , Feminino , Estudos de Associação Genética , Genômica , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Linhagem , Fenótipo , Deleção de Sequência/genética , Adulto JovemRESUMO
Ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC) syndrome is an autosomal dominant form of ectodermal dysplasia associated with limb anomalies and orofacial clefting. The TP63 gene has been shown to be the cause of the disease, and some tentative genotype-phenotype correlations have been reported. We describe a familial case of EEC syndrome, diagnosed in two siblings affected by severe ectrodactyly and mild ectodermal dysplasia, without clefting. Moreover, one of the siblings had a history of delayed developmental milestones in the first years of life. Family history revealed mild hand malformations in the father and grandfather, who were not available for clinical evaluation. The TP63 gene molecular study showed in both siblings a heterozygous H208D mutation, which has not been previously reported to our knowledge, suggesting that this molecular lesion is associated with EEC syndrome without orofacial clefting.
Assuntos
Displasia Ectodérmica/genética , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Mutação/genética , Transativadores/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Criança , Fenda Labial/genética , Fissura Palatina/genética , Feminino , Genótipo , Humanos , Masculino , Fenótipo , Irmãos , Fatores de TranscriçãoAssuntos
Anormalidades Múltiplas/genética , Pálpebras/anormalidades , Adulto , Fenda Labial/genética , Fissura Palatina/genética , Proteínas de Ligação a DNA/genética , Displasia Ectodérmica/genética , Feminino , Humanos , Recém-Nascido , Masculino , Mutação Puntual , Síndrome , Transativadores/genética , Fatores de Transcrição , Proteínas Supressoras de Tumor/genéticaRESUMO
Clinical diagnosis in dysmorphology is made by the recognition of a specific pattern of malformations and through an analytic search for discrete features. We present our personal experience regarding the usefulness of hair morphology as a tool for diagnosis in some metabolic and malformation syndromes. These cases represent only a few illustrative examples; an exhaustive review of the topic can be found elsewhere.
Assuntos
Anormalidades Múltiplas/diagnóstico , Cabelo/anormalidades , Criança , Pré-Escolar , Técnicas e Procedimentos Diagnósticos , Displasia Ectodérmica/diagnóstico , Feminino , Cabelo/anatomia & histologia , Humanos , Masculino , Síndrome dos Cabelos Torcidos/diagnóstico , Doenças Mitocondriais/diagnóstico , SíndromeRESUMO
A new case of the association of the Beckwith-Wiedemann and prune belly syndrome is reported and the aetiology of the syndromes discussed.
