Integrated gene analyses of de novo variants from 46,612 trios with autism and developmental disorders.

Researchers studied genetic changes in nearly 47,000 families to understand autism and developmental delays better. They found 615 genes that may contribute to these conditions and discovered that autism and developmental delays share many of the same genetic causes. The study found no genes specific only to autism, but did find some genes more linked to developmental delays. They also identified genes that affect boys and girls differently, including some that have a greater impact on girls.

This large-scale genetic analysis examined de novo variants from 46,612 families (15,560 with autism, 31,052 with developmental disorders) to identify genes contributing to neurodevelopmental conditions. Researchers found 615 candidate genes linked to neurodevelopmental disorders, with 138 reaching the highest significance threshold. The study revealed five distinct functional gene networks corresponding to different brain development pathways. Notably, no autism-specific genes were identified, while 18 genes showed specific enrichment for developmental disorders.

The analysis also identified 53 genes with specific mutation patterns and 10 genes showing sex-bias, including 4 X-chromosome genes with greater impact in females.

This research supports treating autism and developmental delays as related conditions sharing genetic causes. The identification of sex-biased genes may help explain why these conditions affect boys and girls differently. These findings could improve genetic counseling and may eventually lead to more targeted treatments based on specific genetic profiles.

Sample characteristics and demographic details not provided. Study focuses on de novo variants only, not inherited genetic factors. Clinical phenotype details and severity measures not described in the abstract.

Most genetic studies consider autism spectrum disorder (ASD) and developmental disorder (DD) separately despite overwhelming comorbidity and shared genetic etiology. Here, we analyzed de novo variants (DNVs) from 15,560 ASD (6,557 from SPARK) and 31,052 DD trios independently and also combined as broader neurodevelopmental disorders (NDDs) using three models. We identify 615 NDD candidate genes (false discovery rate [FDR] < 0.05) supported by ≥1 models, including 138 reaching Bonferroni exome-wide significance (< 3.64e-7) in all models. The genes group into five functional networks associating with different brain developmental lineages based on single-cell nuclei transcriptomic data.

We find no evidence for ASD-specific genes in contrast to 18 genes significantly enriched for DD. There are 53 genes that show mutational bias, including enrichments for missense (= 41) or truncating (= 12) DNVs. We also find 10 genes with evidence of male- or female-bias enrichment, including 4 X chromosome genes with significant female burden (,,, and. This large-scale integrative analysis identifies candidates and functional subsets of NDD genes.