Recent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the “de novo paradigm” of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244) and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs. Autism spectrum disorders (ASDs) are genetically heterogeneous neurodevelopmental conditions. Takata et al. analyze de novo mutations (DNMs) in Japanese ASD probands and confirm that the “de novo paradigm” is applicable across cohorts of different ethnicities. They perform integrative analyses of DNMs by combining published datasets, identifying potential disease genes and drug candidates.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)