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Pedigree, linkage and association studies are consistent with heritable variation for complex disease due to the segregation of genetic factors in families and in the population. In contrast, de novo mutations make only minor contributions to heritability estimates for complex traits. Nonetheless, some de novo variants are known to be important in disease etiology. The identification of risk-conferring de novo variants will contribute to the discovery of etiologically relevant genes and pathways and may help in genetic counseling. There is considerable interest in the role of such mutations in complex neuropsychiatric disease, largely driven by new genotyping and sequencing technologies. An important role for large de novo copy number variations has been established. Recently, whole-exome sequencing has been used to extend the investigation of de novo variation to point mutations in protein-coding regions. Here, we consider several challenges for the interpretation of such mutations in the context of their role in neuropsychiatric disease.

Original publication

DOI

10.1038/ng.2555

Type

Journal article

Journal

Nat Genet

Publication Date

03/2013

Volume

45

Pages

234 - 238

Keywords

Autistic Disorder, Exons, Genetic Association Studies, Genetic Linkage, Genetic Predisposition to Disease, Humans, Mutation, Open Reading Frames, Pedigree, Schizophrenia