RESUMO
BACKGROUND: The pathogenicity of copy number variations (CNV) in neurodevelopmental disorders is supported by research literature. However, few studies have evaluated the utility and counseling challenges of CNV analysis in clinic. METHODS: We analyzed the findings of CNV studies from a cohort referred for genetics evaluation of autism spectrum disorders (ASD), developmental disability (DD), and intellectual disability (ID). RESULTS: Twenty-two CNV in 21 out of 115 probands are considered to be pathogenic (18.3%). Five CNV are likely pathogenic and 22 CNV are variants of unknown significance (VUS). We have found seven cases with more than two CNV and two with a complex rearrangement of the 22q13.3 Phelan-McDermid syndrome region. We identified a new and de novo 1q21.3 deletion that encompasses SETDB1, a gene encoding methylates histone H3 on lysine-9 (H3K9) methyltransferase, in a case with ASD. CONCLUSION: We provide evidence to support the value of CNV analysis in etiological evaluation of neurodevelopmental disorders in autism genetics clinic. However, interpretation of the clinical significance and counseling families are still challenging because of the variable penetrance and pleotropic expressivity of CNV. In addition, the identification of a 1q21.3 deletion encompassing SETDB1 provides further support for the role of chromatin modifiers in the etiology of ASD.
Assuntos
Análise em Microsséries , Transtornos do Neurodesenvolvimento/genética , Proteínas Metiltransferases/genética , Adolescente , Algoritmos , Transtorno Autístico/genética , Criança , Pré-Escolar , Cromatina/metabolismo , Hibridização Genômica Comparativa , Aconselhamento , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/genética , Feminino , Deleção de Genes , Rearranjo Gênico , Histona-Lisina N-Metiltransferase , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , LinhagemRESUMO
We report 2 patients with drug-resistant epilepsy caused by KCNT1 mutations who were treated with quinidine. Both mutations manifested gain of function in vitro, showing increased current that was reduced by quinidine. One, who had epilepsy of infancy with migrating focal seizures, had 80% reduction in seizure frequency as recorded in seizure diaries, and partially validated by objective seizure evaluation on EEG. The other, who had a novel phenotype, with severe nocturnal focal and secondary generalized seizures starting in early childhood with developmental regression, did not improve. Although quinidine represents an encouraging opportunity for therapeutic benefits, our experience suggests caution in its application and supports the need to identify more targeted drugs for KCNT1 epilepsies.
