| Title: | Copy-number variants in the contactin-5 gene are a potential risk factor for autism spectrum disorder |
| Journal: | Research in Autism Spectrum Disorders |
| Published: | 1 Nov 2022 |
| DOI: | https://doi.org/10.1016/j.rasd.2022.102055 |
| URL: | https://inserm.hal.science/inserm-03854794/file/Schmilovich%20et%20al%20%28Chaumette%29.pdf |
Publication 10639
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Abstract
Background 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. Method 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. Results 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. Conclusions 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.</p>
23 Authors
- Zoe Schmilovich
- Guillaume Huguet
- Qin He
- Amélie Musa-Johnson
- Elise Douard
- Mor Absa Loum
- Calwing Liao
- Jay P. Ross
- Alexandre Dionne-Laporte
- Dan Spiegelman
- Martineau Jean-Louis
- Zohra Saci
- Caroline Hayward
- Tobias Banaschewski
- Arun Bokde
- Sylvane Desrivieres
- Herve Lemaitre
- Gunter Schumann
- Lan Xiong
- Patrick A. Dion
- Sébastien Jacquemont
- Boris Chaumette
- Guy A. Rouleau
Enabling scientific discoveries that improve human health