Genome-wide analysis identifies a role for common copy number variants in specific language impairment

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.

Understanding Language from a Genomic Perspective

“…In a study involving 376 individuals with dyslexia, there was no difference in CNV frequency between dyslexics and controls, whereas the frequency was increased in people with autism spectrum disorders (ASDs) or ID (51). A screen of >100 SLI cases similarly found no increased burden of rare CNVs but did observe a higher frequency of common CNVs compared to controls (149). Some CNVs are characterized by incomplete penetrance (not all carriers are affected) and variable expressivity (the same variant leads to different disorders in different people), which can make interpretation difficult.…”

Stage 2 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: testing the double hit hypothesis

“…Similarly, while a SNP-based analysis may tag structural rearrangements (deletions and duplications), an alternative approach would be required to fully assess the role of copy number variants. Copy number variants have been reported to play a role in neurodevelopmental disorder ( Girirajan et al , 2011) and developmental language disorders ( Simpson et al , 2015). …”

The role of linguistic and cognitive factors in emotion recognition difficulties in children with ASD, ADHD or DLD

“…, Simpson et al . , Smoller et al . ), and they quite often occur together, which may suggest at least partly shared neurobiological and etiological background (Rommelse et al .…”

“…The present study explores the emotion recognition abilities of children with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and developmental language disorder (DLD). These disorders have similar etiological background consisting of genetic or hereditary factors (Onnisa et al 2018, Simpson et al 2015, Smoller et al 2013, and they quite often occur together, which may suggest at least partly shared neurobiological and etiological background (Rommelse et al 2010, see also Bishop 2010). The growing understanding of the similarities and differences in these three diagnostic groups has also affected the diagnostic criteria of ASD, ADHD and DLD (or specific language impairment-SLI) as they have been undergoing change in both the ICD-11 and the recently published DSM-5 American Psychiatric Association (APA) (2013) classifications.…”