Copy-number variants in the contactin-5 gene are a potential risk factor for autism spectrum disorder

• Published in: Research in autism spectrum disorders 2022-11, Vol.99, p.102055, Article 102055
• Main Authors: Schmilovich, Zoe, Huguet, Guillaume, He, Qin, Musa-Johnson, Amélie, Douard, Elise, Loum, Mor Absa, Liao, Calwing, Ross, Jay P., Dionne-Laporte, Alexandre, Spiegelman, Dan, Jean-Louis, Martineau, Saci, Zohra, Hayward, Caroline, Banaschewski, Tobias, Bokde, Arun, Desrivieres, Sylvane, Lemaitre, Herve, Schumann, Gunter, Xiong, Lan, Dion, Patrick A., Jacquemont, Sébastien, Chaumette, Boris, Rouleau, Guy A.
• Format: Article
• Language: English
• Subjects: CNTN5; CNV; inherited; intronic deletions; neurodevelopment
• ISSN: 1750-9467; 1878-0237
• DOI: 10.1016/j.rasd.2022.102055

Contactin-5 (CNTN5) is a candidate risk gene for autism spectrum disorder (ASD). Previous attempts to associate CNTN5 CNVs 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-scale case-control analyses. A CNTN5 CNV, shared by four brothers in a multiplex family with ASD, was initially identified. We calculated the prevalence and transmission of CNTN5 CNVs in cases across five ASD cohorts (n=15,784). Second, we compared the prevalence of CNTN5 CNVs in cases to their unaffected siblings (n=4,996). Third, we assessed the enrichment of CNTN5 CNVs in cases to extrafamilial controls across three cohorts (n=24,886) and the UK Biobank (n = 459,862). Finally, we evaluated the clinical impact of CNTN5 CNVs in a broad neurodevelopmental disorder cohort and the DECIPHER database. Most (96.7%) CNTN5 CNV deletions (0.193%) and duplications (0.03%) in cases were inherited by a parent that transmitted the variant to their affected and unaffected children at the same rate. We identified a significant enrichment of intronic CNTN5 CNV deletions in cases compared to extrafamilial controls (0.178% versus 0.019%; p-value=1.68E-05; OR:8.51; 95%CI=[2.58-44.21]). There was no difference in CNTN5 CNV enrichment between cases and individuals with NDDs. Intronic CNTN5 CNV deletions are rare, inherited, and intermediate effect size ASD-susceptibility variants that may also confer risk for other neuropsychiatric disorders. We offer a framework to characterize candidate variants that may not be detected through small-scale approaches to implicate intermediate effect size variants in the etiology of ASD. •CNVs encompassing the CNTN5 gene may increase the risk for ASD and broad neurodevelopmental disorders.•CNTN5 CNVs are rare and parents transmit the variant to their children with ASD and unaffected children at the same rate.•Framework to assess the role of rare and intermediate effect-size candidate variants in complex disorders