Genomic architecture of Autism Spectrum Disorder from comprehensive whole-genome sequence annotation

Abstract

Fully understanding the genetic factors involved in Autism Spectrum Disorder (ASD) requires whole-genome sequencing (WGS), which theoretically allows the detection of all types of genetic variants. With the aim of generating an unprecedented resource for resolving the genomic architecture underlying ASD, we analyzed genome sequences and phenotypic data from 5,100 individuals with ASD and 6,212 additional parents and siblings (total n=11,312) in the Autism Speaks MSSNG Project, as well as additional individuals from other WGS cohorts. WGS data and autism phenotyping were based on high-quality short-read sequencing (>30x coverage) and clinically accepted diagnostic measures for ASD, respectively. For initial discovery of ASD-associated genes, we used exonic sequence-level variants from MSSNG as well as whole-exome sequencing-based ASD data from SPARK and the Autism Sequencing Consortium (>18,000 trios plus additional cases and controls), identifying 135 ASD-associated protein-coding genes with false discovery rate <10%. Combined with ASD-associated genes curated from the literature, this list was used to guide the interpretation of all other variant types in WGS data from MSSNG and the Simons Simplex Collection (SSC; n=9,205). We identified ASD-associated rare variants in 789/5,100 individuals with ASD from MSSNG (15%) and 421/2,419 from SSC (17%). Considering the genomic architecture, 57% of ASD-associated rare variants were nuclear sequence-level variants, 41% were nuclear structural variants (SVs) (mainly copy number variants, but also including inversions, large insertions, uniparental isodisomies, and tandem repeat expansions), and 2% were mitochondrial variants. Several of the ASD-associated SVs would have been difficult to detect without WGS, including an inversion disrupting SCN2A and a nuclear mitochondrial insertion impacting SYNGAP1. Polygenic risk scores did not differ between children with ASD in multiplex families versus simplex, and rare, damaging recessive events were significantly depleted in multiplex families, collectively suggesting that rare, dominant variation plays a predominant role in multiplex ASD. Our study provides a guidebook for exploring genotype-phenotype correlations in the 15-20% of ASD families who carry ASD-associated rare variants, as well as an entry point to the larger and more diverse studies that will be required to dissect the etiology in the >80% of the ASD population that remains idiopathic. All data resulting from this study are available to the medical genomics research community in an open but protected manner.

Disruption of DDX53 coding sequence has limited impact on iPSC-derived human NGN2 neurons

“…We have observed a high proportion of ASD-associated deletions across the PTCHD1-AS locus, which may or may not impact DDX53 [8,[22][23][24]. To determine whether DDX53 has a role in the etiology of ASD in the cortex, we undertook a functional analysis of DDX53 in NGN2 differentiated neurons to examine the synaptic phenotype.…”

SCIP: software for efficient clinical interpretation of copy number variants detected by whole-genome sequencing

“…We next evaluated SCIP using a large collection of clinical WGS samples. We assembled this collection from two sources at The Hospital for Sick Children: a cohort of patients with cardiovascular anomalies (primarily congenital heart defects) from the Cardiac Genome Clinic (CGC, n = 316 families) (Reuter et al 2020 ), and a cohort of patients with autism spectrum disorder from the MSSNG Project and analyzed at The Centre for Applied Genomics (TCAG) ( n = 711 families) (Trost et al 2022 ; Yuen et al 2016 ), for a total of 1027 families. Because some families had multiple sequenced siblings, the 1027 families harboured 1188 non-parental WGS samples.…”

“…We also analyzed WGS data from the MSSNG Project, which contains nearly 3000 families sequenced for autism spectrum disorder (Trost et al 2022 ). These samples were analyzed by The Centre for Applied Genomics at The Hospital for Sick Children, aligned to GRCh38/hg38.…”

Gene copy number variation in pediatric mental illness in a general population

“…Here we show specific CNV impacting important neurodevelopmental genes are found in ∼4% of individuals in our community-based sample. From our other research, we anticipate that the clinical findings will nearly double when genome sequencing is used since all classes of genetic variants (sequence-level mutations, smaller CNVs, structural variations, and mitochondrial) are found ( 36 ). Moreover, including polygenic risk score analysis of common genetic variants ( 37-39 ) or gene conservation weighting ( 26, 40 ) may help to further delineate phenotypic expression of traits in penetrant CNV carriers.…”