Functional relationships between recessive inherited genes and genes with de novo variants in autism spectrum disorder

Abstract

Background Both de novo variants and recessive inherited variants were associated with autism spectrum disorder (ASD). This study aimed to use exome data to prioritize recessive inherited genes (RIGs) with biallelically inherited variants in autosomes or X-linked inherited variants in males and investigate the functional relationships between RIGs and genes with de novo variants (DNGs). Methods We used a bioinformatics pipeline to analyze whole-exome sequencing data from 1799 ASD quads (containing one proband, one unaffected sibling, and their parents) from the Simons Simplex Collection and prioritize candidate RIGs with rare biallelically inherited variants in autosomes or X-linked inherited variants in males. The relationships between RIGs and DNGs were characterized based on different genetic perspectives, including genetic variants, functional networks, and brain expression patterns. Results Among the biallelically or hemizygous constrained genes that were expressed in the brain, ASD probands carried significantly more biallelically inherited protein-truncating variants (PTVs) in autosomes (p = 0.038) and X-linked inherited PTVs in males (p = 0.026) than those in unaffected siblings. We prioritized eight autosomal, and 13 X-linked candidate RIGs, including 11 genes already associated with neurodevelopmental disorders. In total, we detected biallelically inherited variants or X-linked inherited variants of these 21 candidate RIGs in 26 (1.4%) of 1799 probands. We then integrated previously reported known or candidate genes in ASD, ultimately obtaining 70 RIGs and 87 DNGs for analysis. We found that RIGs were less likely to carry multiple recessive inherited variants than DNGs were to carry multiple de novo variants. Additionally, RIGs and DNGs were significantly co-expressed and interacted with each other, forming a network enriched in known functional ASD clusters, although RIGs were less likely to be enriched in these functional clusters compared with DNGs. Furthermore, although RIGs and DNGs presented comparable expression patterns in the human brain, RIGs were less likely to be associated with prenatal brain regions, the middle cortical layers, and excitatory neurons than DNGs. Limitations The RIGs analyzed in this study require functional validation, and the results should be replicated in more patients with ASD. Conclusions ASD RIGs were functionally associated with DNGs; however, they exhibited higher heterogeneity than DNGs.

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

“…The gnomAD pRec score, which represents the probability of intolerance to biallelic loss of function, was higher in these genes than other genes (Mann-Whitney test: p=0.0004). Five of these genes ( SYNE1, FAT1, VPS13B, DNAH3, and ITGB4 ) have previously been associated with ASD (Krumm et al, 2015; Wang et al, 2020). ITGB4 was also identified in the TADA+ analysis, suggesting that it may confer ASD susceptibility in a dose-dependent manner.…”

Bioenergetic signatures of neurodevelopmental regression

“…Despite ASD being highly heritable, inherited defects in single genes are rare ( Schaefer et al, 2013 ) and most identified single gene mutations are de novo ( O'Roak et al, 2014 ; Wang et al, 2020 ). Even when both chromosomal microarray and whole exome sequencing are used, the unbiased empirical clinical genetic evaluations demonstrate low yields (−16%) ( Tammimies et al, 2015 ) and only 31% of the time do siblings with ASD have the same de novo single gene mutations ( Yuen et al, 2015 ).…”

Modern Biomarkers for Autism Spectrum Disorder: Future Directions

“…However, despite the high apparent heritability, empirical studies suggest that structural genetic defects account for a minority of ASD cases with empirical studies finding that a genetic disorder can be found in only about 16% of children with ASD using both a chromosomal microarray and whole exome sequencing [20]. In addition, when a variant is found, it is usually de novo rather than inherited [21][22][23][24]. In fact, there is insufficient evidence for a ASD-specific gene or a particular genetic variant with a large effect [25].…”