Copy-Number Variants in The Contactin-5 Gene Are a Potential Risk Factor for Autism Spectrum Disorder - Archive ouverte HAL Access content directly
Journal Articles Research in Autism Spectrum Disorders Year : 2021

Copy-Number Variants in The Contactin-5 Gene Are a Potential Risk Factor for Autism Spectrum Disorder

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Background Contactin-5 (CNTN5) is a candidate risk gene for autism spectrum disorder (ASD), yet previous attempts to associate copy number variants (CNVs) encompassing CNTN5 with ASD-susceptibility were limited by insufficient statistical power. Here, we aim to clarify the putative association between CNTN5 CNVs and ASD-risk using large samples. Methods First, we calculated the prevalence and transmission of CNTN5 CNVs in ASD across three ASD cohorts (SSC, MSSNG, and SPARK), the cases reported in the Mercati et al. study, and the BBGRE database (n = 16,607). Second, we modelled their transmission in children with ASD compared to their unaffected siblings. Third, we assessed their frequency in cases with ASD compared to unselected population controls (n = 24,898) and replicated the findings in UK Biobank (UKBB), an independent general population cohort (n = 459,855). Finally, we evaluated the clinical impact of CNTN5 CNVs by assessing their enrichment in a broad neurodevelopmental disorder (NDD) cohort, and the clinical profile of CNTN5 CNV carriers in the DECIPHER database. Results The prevalence of CNTN5 exonic deletions and duplications was stable across ASD and across unselected cohorts (0.042% and 0.020%, respectively). We found a significant enrichment of intronic CNTN5 deletions CNVs in ASD compared to unselected controls (0.175% and 0.004%, respectively). CNVs in most cases with ASD (29 out of 30, 96.7%) were inherited. Parents transmitted the variants to their affected and unaffected children with the same frequency. No differences in exonic CNTN5 CNVs enrichment between cases with ASD compared to individuals with NDDs was observed. Limitations The lack of phenotypic data available for unaffected family members of probands with ASD limits the potential to assess whether CNTN5 CNVs segregate with other neuropsychiatric or sub-threshold autistic traits. Different genotyping or sequencing technologies may affect the differences in CNTN5 CNV prevalence across cohorts. Conclusion CNTN5 CNVs are rare inherited ASD susceptibility variants. They may also confer risk for other neuropsychiatric disorders. We offer a powerful framework to investigate candidate susceptibility variants that may not be detected through small-scale approaches. This approach may reveal more intermediate effect-size variants that are implicated in the etiology of ASD.
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Dates and versions

inserm-03854794 , version 1 (16-11-2022)



Zoe Schmilovich, Guillaume Huguet, Qin He, Amélie Musa-Johnson, Elise Douard, et al.. Copy-Number Variants in The Contactin-5 Gene Are a Potential Risk Factor for Autism Spectrum Disorder. Research in Autism Spectrum Disorders, 2021, 99, pp.102055. ⟨10.21203/⟩. ⟨inserm-03854794⟩
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