RESUMEN
Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants have been identified in affected individuals, their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations have not been well characterized in matched unaffected controls, and such data are vital to the interpretation of de novo coding mutations observed in probands. Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit), a result that is highly unlikely by chance.
Asunto(s)
Trastorno Autístico/genética , Exoma/genética , Exones/genética , Predisposición Genética a la Enfermedad/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Canales de Sodio/genética , Alelos , Codón sin Sentido/genética , Heterogeneidad Genética , Humanos , Canal de Sodio Activado por Voltaje NAV1.2 , Sitios de Empalme de ARN/genética , HermanosRESUMEN
Contactins and Contactin-Associated Proteins, and Contactin-Associated Protein-Like 2 (CNTNAP2) in particular, have been widely cited as autism risk genes based on findings from homozygosity mapping, molecular cytogenetics, copy number variation analyses, and both common and rare single nucleotide association studies. However, data specifically with regard to the contribution of heterozygous single nucleotide variants (SNVs) have been inconsistent. In an effort to clarify the role of rare point mutations in CNTNAP2 and related gene families, we have conducted targeted next-generation sequencing and evaluated existing sequence data in cohorts totaling 2704 cases and 2747 controls. We find no evidence for statistically significant association of rare heterozygous mutations in any of the CNTN or CNTNAP genes, including CNTNAP2, placing marked limits on the scale of their plausible contribution to risk.
Asunto(s)
Trastorno Autístico/genética , Contactinas/genética , Estudios de Asociación Genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Trastorno Autístico/patología , Codón sin Sentido , Variaciones en el Número de Copia de ADN , Predisposición Genética a la Enfermedad , Humanos , Mutación Puntual , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Eliminación de SecuenciaRESUMEN
Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0-2.7; p = 0.03), are more common in female probands (p = 0.02), are enriched among genes encoding FMRP targets (p = 6 × 10(-9)), and arise predominantly on the paternal chromosome (p < 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.
Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/genética , Mutación del Sistema de Lectura , Eliminación de Secuencia , Niño , Trastornos Generalizados del Desarrollo Infantil/sangre , Trastornos Generalizados del Desarrollo Infantil/diagnóstico , ADN/sangre , ADN/genética , Proteínas de Unión al ADN/genética , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Proteínas de Unión al GTP/genética , Humanos , Masculino , Proteínas del Tejido Nervioso/genética , Linaje , Fenotipo , Factores SexualesRESUMEN
We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6-12.0, p = 2.4 × 10(-7)). We estimate there are 130-234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1.