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1.
Genet Med ; 17(12): 995-1001, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25790160

RESUMO

PURPOSE: The Scripps Idiopathic Diseases of Man (IDIOM) study aims to discover novel gene-disease relationships and provide molecular genetic diagnosis and treatment guidance for individuals with novel diseases using genome sequencing integrated with clinical assessment and multidisciplinary case review. Here we describe the operational protocol and initial results of the IDIOM study. METHODS: A total of 121 cases underwent first-tier review by the principal investigators to determine whether the primary inclusion criteria were satisfied, 59 (48.8%) underwent second-tier review by our clinician-scientist review panel, and 17 patients (14.0%) and their family members were enrolled. RESULTS: 60% of cases resulted in a plausible molecular diagnosis, and 18% of cases resulted in a confirmed molecular diagnosis. Two of three confirmed cases led to the identification of novel gene-disease relationships. In the third confirmed case a previously described but unrecognized disease was revealed. In all three confirmed cases a new clinical management strategy was initiated based on the genetic findings. CONCLUSION: Genome sequencing provides tangible clinical benefit for individuals with idiopathic genetic disease, not only in the context of molecular genetic diagnosis of known rare conditions but also in cases where prior clinical information regarding a new genetic disorder is lacking.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Genoma Humano , Patologia Molecular , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Doenças Genéticas Inatas/terapia , Genômica , Humanos , Lactente , Masculino , Doenças Raras/diagnóstico , Doenças Raras/genética , Doenças Raras/terapia , Análise de Sequência de DNA , Adulto Jovem
2.
Ann Neurol ; 76(4): 529-540, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25164438

RESUMO

OBJECTIVE: Numerous studies have demonstrated increased load of de novo copy number variants or single nucleotide variants in individuals with neurodevelopmental disorders, including epileptic encephalopathies, intellectual disability, and autism. METHODS: We searched for de novo mutations in a family quartet with a sporadic case of epileptic encephalopathy with no known etiology to determine the underlying cause using high-coverage whole exome sequencing (WES) and lower-coverage whole genome sequencing. Mutations in additional patients were identified by WES. The effect of mutations on protein function was assessed in a heterologous expression system. RESULTS: We identified a de novo missense mutation in KCNB1 that encodes the KV 2.1 voltage-gated potassium channel. Functional studies demonstrated a deleterious effect of the mutation on KV 2.1 function leading to a loss of ion selectivity and gain of a depolarizing inward cation conductance. Subsequently, we identified 2 additional patients with epileptic encephalopathy and de novo KCNB1 missense mutations that cause a similar pattern of KV 2.1 dysfunction. INTERPRETATION: Our genetic and functional evidence demonstrate that KCNB1 mutation can result in early onset epileptic encephalopathy. This expands the locus heterogeneity associated with epileptic encephalopathies and suggests that clinical WES may be useful for diagnosis of epileptic encephalopathies of unknown etiology.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia/genética , Predisposição Genética para Doença/genética , Mutação de Sentido Incorreto/genética , Canais de Potássio Shab/genética , Animais , Biotinilação , Células CHO , Criança , Pré-Escolar , Cricetulus , Feminino , Humanos , Masculino , Potenciais da Membrana/genética , Técnicas de Patch-Clamp , Fenótipo , Transfecção
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