Patterns and rates of exonic de novo mutations in autism spectrum disorders.
Nature
; 485(7397): 242-5, 2012 Apr 04.
Article
en En
| MEDLINE
| ID: mdl-22495311
ABSTRACT
Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Trastorno Autístico
/
Factores de Transcripción
/
Exones
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Predisposición Genética a la Enfermedad
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Proteínas de Unión al ADN
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Mutación
Tipo de estudio:
Observational_studies
/
Prognostic_studies
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Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Nature
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos