Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 patients and >2,867 controls. We report 91 genes with an excess of de novo mutations or private disruptive mutations in 5.7% of patients, including 38 novel NDD genes. Drosophila functional assays of a subset bolster their involvement in NDDs. We identify 25 genes that show a bias for autism versus intellectual disability and highlight a network associated with high-functioning autism (FSIQ>100). Clinical follow-up for NAA15, KMT5B, and ASH1L reveals novel syndromic and non-syndromic forms of disease.

Objective Epidemiological data have suggested maternal infection and fever to be associated with increased risk of ASD. Animal studies show that gestational infections perturb fetal brain development and result in offspring with the core features of autism and have demonstrated that behavioral effects of maternal immune activation (MIA) are dependent on genetic susceptibility. The goal of this study was to explore the impact of ASD-associated CNVs and prenatal maternal infection on clinical severity of ASD within a dataset of prenatal history and complete genetic and phenotypic findings. Method We analyzed data from the Simons Simplex Collection sample including 1971 children with a diagnosis of ASD aged 4 to 18 years who underwent array CGH screening. Information on infection and febrile episodes during pregnancy was collected through parent interview. ASD severity was clinically measured through parent-report interview and questionnaires. Results We found significant interactive effects between presence of CNVs and maternal infection during pregnancy on autistic symptomatology, such that individuals with CNVs and history of maternal infection demonstrated increased rates of social communicative impairments and repetitive/restricted behaviors. In contrast, no significant interactions were found between presence of CNVs and prenatal infections on cognitive and adaptive functioning of individuals with ASD. Conclusion Our findings support a gene-environment interaction model of autism impairment, in that individuals with ASD-associated CNVs are more susceptible to the effects of maternal infection and febrile episodes in pregnancy on behavioral outcomes, and suggest that these effects are specific to ASD rather than to global neurodevelopment.

Autism spectrum disorder (ASD) is a behaviorally heterogeneous disorder with a strong genetic component, as evidenced by decades of twin and family studies. In recent years, enhanced methods of genomic sequencing have revealed that structural variation and mutations to both coding and non-coding regions of single, candidate genes may account for more than 30% of ASD cases. The current review highlights a genotype-first approach that builds upon these molecular findings to parse the heterogeneity of ASD. Advantages of this approach include strong potential for precision medicine diagnosis and treatment, as well as opportunity to advance basic science research on neurodevelopmental disorders. Psychosocial benefits of identifying genetic subtypes of ASD have already been realized through social networking, comprehensive clinical phenotyping, and increased awareness among providers of rare genetic mutations.

Approximately one third of children with autism spectrum disorder (ASD) reportedly lose skills within the first three years, yet a causal mechanism remains elusive. Considering evidence of strong genetic effects for ASD and findings that distinct phenotypes in ASD associate with specific genetic events, we examined rates of parent-reported regression in the Simons Simplex Collection with likely gene disrupting (LGD) mutations from five distinct classes: FMRP target genes, genes encoding chromatin modifiers, genes expressed preferentially in embryos, genes encoding postsynaptic density proteins, and essential genes. Children with ASD and mutations in postsynaptic density genes were more likely to experience regression, while a trend suggested that children with ASD and mutations in embryonic genes were less likely to have skill losses.