Abstract
An exploratory genome-wide copy number variant (CNV) study was performed in 127 independent cases with specific language impairment (SLI), their first-degree relatives (385 individuals) and 269 population controls. Language-impaired cases showed an increased CNV burden in terms of the average number of events (11.28 vs 10.01, empirical P=0.003), the total length of CNVs (717 vs 513 Kb, empirical P=0.0001), the average CNV size (63.75 vs 51.6 Kb, empirical P=0.0005) and the number of genes spanned (14.29 vs 10.34, empirical P=0.0007) when compared with population controls, suggesting that CNVs may contribute to SLI risk. A similar trend was observed in first-degree relatives regardless of affection status. The increased burden found in our study was not driven by large or de novo events, which have been described as causative in other neurodevelopmental disorders. Nevertheless, de novo CNVs might be important on a case-by-case basis, as indicated by identification of events affecting relevant genes, such as ACTR2 and CSNK1A1, and small events within known micro-deletion/-duplication syndrome regions, such as chr8p23.1. Pathway analysis of the genes present within the CNVs of the independent cases identified significant overrepresentation of acetylcholine binding, cyclic-nucleotide phosphodiesterase activity and MHC proteins as compared with controls. Taken together, our data suggest that the majority of the risk conferred by CNVs in SLI is via common, inherited events within a ‘common disorder–common variant' model. Therefore the risk conferred by CNVs will depend upon the combination of events inherited (both CNVs and SNPs), the genetic background of the individual and the environmental factors.
Highlights
Specific language impairment (SLI) is a developmental disorder that, in the absence of neurological deficits, affects an individual’s spoken and/or receptive language acquisition
We explore the contribution of copy number variant (CNV) to SLI, by studying a set of families collected by the SLI Consortium (SLIC)
Burden analysis 1432 ‘high-confidence’ CNVs were identified in 127 independent cases (11.3 per individual), compared with 4081 in 385 SLIC first-degree relatives (10.6 per individual) and 2693 in 269 population control samples (10.01 per individual)
Summary
Specific language impairment (SLI) is a developmental disorder that, in the absence of neurological deficits, affects an individual’s spoken and/or receptive language acquisition. SLI is a common but genetically complex disorder with an estimated prevalence of up to 7%1 and shows significant overlap with autism, dyslexia and ADHD, both phenotypically[2] and genetically.[3,4] Like many common disorders, the majority of the genetic risk for SLI is expected to be conferred by combinations of common genetic variants that is, the ‘common disorder–common variant’ model.[5] a growing body of evidence suggests that single nucleotide variants alone do not explain the heritability of complex traits (the ‘missing heritability’) and that the underlying aetiology may include other factors such as copy number variants (CNVs), rare variants and epigenetic modifications.[6] Studies have found that individuals with autism or ADHD generally have an increased burden of rare CNVs compared with controls[7,8,9] and that the severity of phenotype across neurodevelopmental disorders may be positively correlated with the burden of large CNVs.[10] The ‘burden’ of CNVs can be considered in many ways, for example, the number of CNVs an individual carries, the average size of CNVs, the total size of CNVs across the genome or the number of genes affected by CNV events. Other CNVs are not recurrent within a disorder but private to a particular family, presumably contributing to a biological pathway that is shared in other individuals
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