Gene Variants Involved in Nonsense-Mediated mRNA Decay Suggest a Role in Autism Spectrum Disorder

Abstract

Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition with unclear etiology. Many genes have been associated with ASD risk, but the underlying mechanisms are still poorly understood. An important post-transcriptional regulatory mechanism that plays an essential role during neurodevelopment, the Nonsense-Mediated mRNA Decay (NMD) pathway, may contribute to ASD risk. In this study, we gathered a list of 46 NMD factors and regulators and investigated the role of genetic variants in these genes in ASD. By conducting a comprehensive search for Single Nucleotide Variants (SNVs) in NMD genes using Whole Exome Sequencing data from 1828 ASD patients, we identified 270 SNVs predicted to be damaging in 28.7% of the population. We also analyzed Copy Number Variants (CNVs) from two cohorts of ASD patients (N = 3570) and discovered 38 CNVs in 1% of cases. Importantly, we discovered 136 genetic variants (125 SNVs and 11 CNVs) in 258 ASD patients that were located within protein domains required for NMD. These gene variants are classified as damaging using in silico prediction tools, and therefore may interfere with proper NMD function in ASD. The discovery of NMD genes as candidates for ASD in large patient genomic datasets provides evidence supporting the involvement of the NMD pathway in ASD pathophysiology.

SOX7: Novel Autistic Gene Identified by Analysis of Multi-Omics Data

“…XRN2 has been found to play a role in regulating miRNA expression in neurons specifically, and altered miRNA expression regulation has been investigated as a potential mechanism for autism susceptibility (Kinjo et al 2013;Hicks and Middleton 2016;Ghahramani Seno et al 2011;Wu et al 2016;Abu-Elneel et al 2008). Likewise, disruption of proper RNA metabolism as a result of altered expression of RNA binding proteins has been implicated in neurological disease as a whole, and the XRN gene family is involved in nonsense-mediated decay of mRNA, a process that has been implicated in autism pathophysiology (Nussbacher et al 2019;Marques et al 2022). Previous GWAS have reported SNPs in the region containing XRN2 to be significantly associated with ASD, affirmed by genebased analysis using MAGMA (Grove et al 2019).…”

SOX7: Novel Autistic Gene Identified by Analysis of Multi-Omics Data

“…XRN2 has been found to play a role in regulating miRNA expression in neurons specifically, and altered miRNA expression regulation has been investigated as a potential mechanism for autism susceptibility ( Abu-Elneel et al, 2008 ; Ghahramani Seno et al, 2011 ; Hicks & Middleton, 2016 ; Kinjo et al, 2013 ; Wu et al, 2016 ). Likewise, disruption of proper RNA metabolism as a result of altered expression of RNA binding proteins has been implicated in neurological disease as a whole, and the XRN gene family is involved in nonsense-mediated decay of mRNA, a process that has been implicated in autism pathophysiology ( Marques et al, 2022 ; Nussbacher et al, 2019 ). Previous GWAS have reported SNPs in the region containing XRN2 to be significantly associated with ASD, affirmed by gene-based analysis using MAGMA ( Grove et al, 2019 ).…”

Group Theory of Messenger RNA Metabolism and Disease

“…Genome-scale metabolic pathways, genome-environment interactions, the immune response, post-transcriptional regulatory mechanisms, and oncohistones represent aspects of a research field connecting the heritable genetic code to other biological codes. [1][2][3][4][5][6] The aforementioned genetic code is defined precisely as a noninjective map from the 64 codons to the 20 amino acids. Both finite groups and quantum groups have leading roles in modeling this code.…”