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.
Highlights
Autism Spectrum Disorder (ASD) is a clinically heterogeneous neurodevelopmental disorder characterized by impaired social communication skills along with repetitive and restricted behaviors and interests [1]
We identified 46 experimentally validated genes encoding core Nonsense-Mediated mRNA Decay (NMD) factors and regulators (Table 1 and Figure 1) through manual curation of a gene list obtained by enrichment analysis and literature review
We examined the EMBL-EBI Expression Atlas to assess whether these genes are expressed during early brain development, and we confirmed that all genes are expressed in the forebrain, midbrain and hindbrain in the first 4 to 8 post-conception weeks (PCW) and in the cerebral cortex in the age range of 8–17 PCW
Summary
Autism Spectrum Disorder (ASD) is a clinically heterogeneous neurodevelopmental disorder characterized by impaired social communication skills along with repetitive and restricted behaviors and interests [1]. ASD is relatively common, with a median estimated prevalence worldwide of 1–2% [2], and has a major social and economic impacts in families and society. The pathophysiology of this disease is still unclear, precluding the development of effective therapies. Genetic factors account for 50 to 80% of the familial. ASD risk [3,4], but genetic determinants are still not fully known. Many studies have shown that Copy Number Variants (CNVs) and Single Nucleotide Variants (SNVs) are associated with an increased risk of developing ASD. De novo, inherited, rare and common variants in hundreds of genes have been implicated in the etiology of this disease [5–11]
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