Abstract
BackgroundBoth 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).MethodsWe 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.ResultsAmong 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.LimitationsThe RIGs analyzed in this study require functional validation, and the results should be replicated in more patients with ASD.ConclusionsASD RIGs were functionally associated with DNGs; however, they exhibited higher heterogeneity than DNGs.
Highlights
Both de novo variants and recessive inherited variants were associated with autism spectrum disorder (ASD)
Prioritization of ASD‐associated recessive inherited genes (RIGs) Because biallelically inherited and X-linked inherited protein-truncating variants (PTVs) significantly differed between the probands and unaffected siblings, we focused on these PTVs to further prioritize candidate genes and filtered them, as the following standard: (1) PTVs recorded as benign variants in the ClinVar database; (2) X-linked inherited PTVs that were present in > 10 males in the Genome aggregation database (gnomAD) database; (3) genes in autosomes harboring biallelically inherited PTVs in the unaffected siblings or genes in the X chromosome harboring X-linked inherited PTVs in the unaffected male siblings; and (4) genes in the X chromosome with a probability of loss-of-function intolerance < 0.5, as sourced from the gnomAD database
Because autosomal biallelically inherited variants shared between probands and their unaffected siblings are less likely to contribute to ASD etiology, they were removed from burden analysis, only proband- and sibling-specific inherited variants were included (Table 1)
Summary
Both de novo variants and recessive inherited variants were associated with autism spectrum disorder (ASD). Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder with a global prevalence of 1% and is clinically diagnosed based on social impairment, repetitive behaviors and restricted interests [1]. In addition to these core symptoms, other variable traits in patients with ASD include neuropsychiatric comorbidities such as intellectual disability (ID) and developmental delay [2], leading to marked clinical heterogeneity. Numerous de novo variants (DNVs), protein-truncating variants (PTVs), have been detected, and several exome-wide significant genes with DNVs (DNGs) have been elucidated, contributing to a better understanding of the genetic causes of ASD. We focused on DNVs to explore the genetic architecture and genotype– phenotype correlations in Chinese ASD patients [29,30,31], demonstrating that analyzing DNG-expression patterns and functional networks could provide clues to elucidate the ASD etiology and subtypes [32,33,34]
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