Rare coding variation provides insight into the genetic architecture and phenotypic context of autism.

Scientists studied the DNA of over 63,000 people to find genes linked to autism. They discovered 72 genes that are strongly connected to autism through rare genetic changes. Different types of genetic changes contribute differently to autism risk. Interestingly, genes linked to general developmental delays affect early brain development, while autism-specific genes are more active in older brain cells and share similarities with genes linked to schizophrenia.

This large-scale meta-analysis examined rare genetic variants in 63,237 individuals to understand autism's genetic architecture. Researchers identified 72 genes strongly associated with autism, with protein-truncating variants contributing most evidence (57.5%), followed by damaging missense variants (21.1%) and copy number variants (8.44%). When combined with developmental delay data (91,605 additional individuals), 373 genes were identified as associated with autism/developmental delay. Importantly, genes associated with developmental delay were enriched in early brain development pathways, while autism-specific genes were more active in maturing neurons and overlapped with schizophrenia-associated genes, suggesting shared biological pathways between these neuropsychiatric conditions.

Findings support genetic heterogeneity in autism and may inform precision medicine approaches. The overlap with schizophrenia genes suggests potential shared therapeutic targets. Results could guide genetic counseling and risk assessment, though clinical translation requires further validation studies.

Sample size not clearly reported. Study focused on rare variants, which may not capture common genetic contributions to autism. Functional validation of identified genes not provided. Clinical phenotyping depth not described.

Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk.

Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.