Patterns and rates of exonic de novo mutations in autism spectrum disorders

By Benjamin M. Neale, Y. Kou, Li Liu, Avi Ma’ayan, Kaitlin E. Samocha, A. Sabo, Chiao-Feng Lin, C. Stevens, Li-San Wang, Vladimir Makarov and 49 more. 2012

1,772 citations recorded by the source corpus.

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.

Subfields: Cognitive Neuroscience, Genetics

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Citations in the corpus

Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism (2013, neutral): “…(599 quartets, 444 trios) from a combination of published data (987 families; 543 quartets, 444 trios) (Iossifov et al., 2012; Kong et al., 2012; Neale et al., 2012; O’Roak et al., 2012b) and exome sequencing of an additional 56 quartets from the Simons Simplex Collection (SSC), a…”
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (2019, background): “TADA requires a mutational model (Sanders et al., 2012; Neale et al., 2012; Samocha et al., 2014) which accounts for gene size and sequence composition to obtain an expectation for mutations per gene, given sample size.”
Integrative omics for health and disease (2018, background): “For instance, in patients with autism spectrum disorder (ASD), genes harbouring de novo missense or nonsense mutations are enriched for genes with high degrees of connectivity in protein–protein interaction networks to all other genes and particularly previously ASD-implicated genes 30 .”
Low concordance of multiple variant-calling pipelines: practical implications for exome and genome sequencing (2013, background): “Although most studies utilizing NGS data to date have focused on ‘quads’ or ‘trios’ [47-51], studying large and/or consanguineous families can maximize the utility of filtering strategies and statistical approaches for identifying disease-contributory variants in genetic disease [52].”
Diagnostic exome sequencing in persons with severe intellectual disability. (2012, methodology): “31 considered to be brain expressed if the log2 intensity was ≥6 for a minimum of three periods as described by Neale et al.(13) (referred to as B).”
Whole Genome Sequencing in Autism Identifies Hotspots for De Novo Germline Mutation (2012, positive): “…correlated with mutation rate variation in a genome-wide data set from two trios (Conrad et al., 2011) (Figure 4B) and exome data sets from four independent trio-based studies of autism (Iossifov et al., 2012; Neale et al., 2012; O’Roak et al., 2011, 2012; Sanders et al., 2012) (Figures 4C and 4D).”
Regional missense constraint improves variant deleteriousness prediction (2017, background): “…focused on neurodevelopmental disorders, such as intellectual disability 1-3 , developmental delay 4,5 , epileptic encephalopathy 6 , and autism spectrum disorders 7-12 —to evaluate the role of de novo variation in the hope of identifying genes and pathways relevant to disease etiology.”
Genic Intolerance to Functional Variation and the Interpretation of Personal Genomes (2013, positive): “We then analysed missense de novo mutations observed in the ID, EE, and ASD studies referenced earlier [9– 15].”
Using deep mutational scanning to benchmark variant effect predictors and identify disease mutations (2020, neutral): “…nonsynonymous single nucleotide variant (SNV) per protein-coding gene (Rauch et al , 2012), while de novo mutations lead to roughly one new nonsynonymous SNV per child not observed in either parent (de Ligt et al , 2012; Neale et al , 2012; Epi4K Consortium et al , 2013; Fitzgerald et al , 2015).”
Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder (2016, background): “We demonstrated the accuracy and utility of our genome-wide complement of autism-associated genes by (5) validating these predictions with de novo autism-associated mutations from an independent sequencing study, elucidating the spatiotemporal developmental gene-expression patterns of top-ranked aut”
Searching for missing heritability: Designing rare variant association studies (2014, background): “For example, CHD8 was associated with autism with mental retardation (prevalence < 1/300) (52) based on the observation of de novo disruptive mutations in 3 of 1,078 cases (53, 54).”