Abstract
Dissecting the genetic susceptibility to intellectual disability (ID) based on de novo mutations (DNMs) will aid our understanding of the neurobiological and genetic basis of ID. In this study, we identify 63 high-confidence ID genes with q-values < 0.1 based on four background DNM rates and coding DNM data sets from multiple sequencing cohorts. Bioinformatic annotations revealed a higher burden of these 63 ID genes in FMRP targets and CHD8 targets, and these genes show evolutionary constraint against functional genetic variation. Moreover, these ID risk genes were preferentially expressed in the cortical regions from the early fetal to late mid-fetal stages. In particular, a genome-wide weighted co-expression network analysis suggested that ID genes tightly converge onto two biological modules (M1 and M2) during human brain development. Functional annotations showed specific enrichment of chromatin modification and transcriptional regulation for M1 and synaptic function for M2, implying the divergent etiology of the two modules. In addition, we curated 12 additional strong ID risk genes whose molecular interconnectivity with known ID genes (q-values < 0.3) was greater than random. These findings further highlight the biological convergence of ID risk genes and help improve our understanding of the genetic architecture of ID.
Highlights
Intellectual disability (ID) is a complex neurodevelopmental disorder characterized by notable deficits in intellectual functioning and adaptive behavior (Ropers, 2010; Musante and Ropers, 2014) with a prevalence of approximately 1% of the world’s population (Maulik et al, 2011)
After excluding non-exonic variants and common variants with MAF ≥ 0.001 based on different public databases (ExAC, UK10K, 1000 Genomes, and ESP6500), we focused on 2,094 de novo mutations (DNMs) located in the coding regions; these DNMs consisted of 1924 de novo single nucleotide variants (SNVs) and 170 de novo indels (Supplementary Table S2)
We found 63 candidate genes with q < 0.1 (63/71, 88.7%) that harbored more than one DNM and could be found simultaneously by any three of the background DNMRs, and we defined these as high-confidence risk genes
Summary
Intellectual disability (ID) is a complex neurodevelopmental disorder characterized by notable deficits in intellectual functioning and adaptive behavior (Ropers, 2010; Musante and Ropers, 2014) with a prevalence of approximately 1% of the world’s population (Maulik et al, 2011). DNMs have been identified as an important source of novel risk genes and provide further insight into the genetic landscape of ID (Hamdan et al, 2014; Lelieveld et al, 2016; Vissers et al, 2016). Statistical analyses of larger cohorts have demonstrated that the candidate genes identified from patients with severe ID often harbor an excess number of loss-of-function (LoF) or functional DNMs with a potentially greater disruptive effect on protein function than expected (Gilissen et al, 2014; Lelieveld et al, 2016).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
