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Exome Sequencing of 457 Autism Families Recruited Online Provides Evidence for Autism Risk Genes

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Exome Sequencing of 457 Autism Families Recruited Online Provides Evidence for Autism Risk Genes

Pamela Feliciano et al. NPJ Genom Med.


Autism spectrum disorder (ASD) is a genetically heterogeneous condition, caused by a combination of rare de novo and inherited variants as well as common variants in at least several hundred genes. However, significantly larger sample sizes are needed to identify the complete set of genetic risk factors. We conducted a pilot study for SPARK ( of 457 families with ASD, all consented online. Whole exome sequencing (WES) and genotyping data were generated for each family using DNA from saliva. We identified variants in genes and loci that are clinically recognized causes or significant contributors to ASD in 10.4% of families without previous genetic findings. In addition, we identified variants that are possibly associated with ASD in an additional 3.4% of families. A meta-analysis using the TADA framework at a false discovery rate (FDR) of 0.1 provides statistical support for 26 ASD risk genes. While most of these genes are already known ASD risk genes, BRSK2 has the strongest statistical support and reaches genome-wide significance as a risk gene for ASD (p-value = 2.3e-06). Future studies leveraging the thousands of individuals with ASD who have enrolled in SPARK are likely to further clarify the genetic risk factors associated with ASD as well as allow accelerate ASD research that incorporates genetic etiology.

Keywords: Autism spectrum disorders; Behavioural genetics; Medical genomics.

Conflict of interest statement

Competing interestsM.S. has received research funding from Roche, Novartis, Pfizer, Aucta, Navitor, Rugen, Ibsen, Neuren, LAM Therapeutics, Quadrant Biosciences and has served on the Scientific Advisory Board of Sage Therapeutics, Roche and Takeda. D.H.G. receives research funding from Takeda Pharmaceuticals, and consulting fees or equity participation for scientific advisory board work from Ovid Therapeutics, Axial Bio-therapeutics, Acurastem, and Falcon Computing. E.E.E. is on the scientific advisory board (SAB) of DNAnexus, Inc. All other authors declare no competing interests.


Fig. 1
Fig. 1
Meta-analysis using the TADA framework identifies 34 genes with a false discovery rate (FDR) of ≤0.2. Known ASD genes are defined as those with SFARI Gene score ≤2 or implicated in a previous TADA meta-analysis (FDR ≤ 0.1) and known NDD genes are those listed in the DDG2P database and are colored orange. Deleterious missense (D-mis) variants are defined by CADD score ≥25. A total of 34 genes with at least one de novo damaging variant observed in SPARK pilot trios achieve an FDR ≤ 0.2 after meta-analysis with published trios (total n = 5238). Fourteen genes are not classified as known ASD or NDD genes. Six genes (BRSK2, ITSN1, FEZF2, PAX5, DMWD, and CPZ) that have an FDR ≤ 0.1 only after inclusion of SPARK de novo variants are highlighted. The asterisk symbol indicates genes that are not constrained (pLI < 0.5)
Fig. 2
Fig. 2
Network analysis and gene expression of candidate ASD risk genes. a STRING networks of forecASD genes, b STRING networks of known ASD genes, and c gene expression of human fetal cortex at postconceptual weeks (PCW) 15–16. Known ASD genes are defined as those with a SFARI Gene scores ≤2 (84 genes, indicated as SFARI) or implicated in a previous TADA meta-analysis at an FDR ≤ 0.1 (65 genes, indicated as TADA). The enrichment for each gene was measured by the t-statistics comparing the expression level in each layer against all other layers. The enrichment of a gene set is the mean of t-statistics of its genes. Two candidate ASD risk genes (PAX5 and KDM1B) are not shown due to the low expression levels in human developing cortex (RPKM <1 for at least 20% available neocortical samples in BrainSpan). Data were extracted from Supplementary Tables of Parikshak et al. Laminae abbreviations: marginal zone (MZ), outer/inner cortical plate (CPo/CPi), subplate (SP), intermediate zone (IZ), outer/inner subventricular zone (SZo/SZi), ventricular zone (VZ)

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