Contactin-5 Copy-Number Variant Is an Inherited Risk Factor for Autism Spectrum Disorder

Background: The genetic contribution of Autism is high with a heritability of 60%. Identifying the genetic factors associated with this disorder is limited by its polymorphic and genetic heterogeneity. Genetic research has focused on rare variants with very large effect size including deletions and duplications of the genome, known as copy-number variants (CNVs). CNVs with intermediate effect size also play a less understood role in the underlying genetic architecture of the disorder. A multiplex family with three affected children with Autism Spectrum Disorder (ASD), a sibling with a neurodevelopmental condition, and an unaffected father were reported to all be carrying a CNV in the Contactin-5 (CNTN5) gene. The protein products of CNTN5 encodes a neuronal cell adhesion molecule and promotes neurite outgrowth, suggesting the gene’s potential role in brain disorders, however, its impact has not yet been demonstrated.

Objectives: This study aims to determine whether CNVs in this gene contribute to the risk for ASD. We examine the penetrance and prevalence of CNTN5 CNVs in affected individuals with ASD and their unaffected siblings, as well as the general population.

Methods: Bioinformatic tools were used to explore six distinct databases. Microarray data from the Simon Simplex Collection (SSC) (n=2587) was used to distinguish CNTN5 CNV prevalence between probands with ASD and their unaffected siblings. A novel structural variant segregation script identified the variant’s inheritance pattern. Generation Scotland and IMAGEN databases (n=7511) were used to compare the prevalence of CNTN5 CNVs between probands and the general population. Copy-number variants from Montreal’s Ste-Justine Hospital (n=16,000) were used to validate the SSC data findings. DECIPHER, a database of individuals (n=27,000) with rare genetic diseases, was used to determine the frequency of de novo CNVs. Database of Genomic Variants (DGV) was used to determine the frequency of CNTN5 CNVs within the general population.

Results: A significant overrepresentation of deletion CNVs within the exonic region of CNTN5 in the probands (n=4/2587) from the SSC, compared to the general population (n=1/7511) (Fisher test p=0.01, Odds Ratio:11.6), was identified. The prevalence of deletion CNTN5 CNVs in ASD probands and their unaffected siblings in the SSC cohort is 0.15%. An identical incomplete penetrance pattern of CNTN5 variants compared to the reported multiplex family was observed in the SSC database. All (n=4) of the deletion CNTN5 CNVs in the probands from the SSC were inherited from phenotypically normal parents; none arose de novo. Incomplete penetrance was noted, as CNVs in CNTN5 were observed in both probands and their unaffected siblings. Interestingly, analysis of the DECIPHER database suggests that 52.6% of the CNV deletions and duplications of CNTN5 (n=10/19) seen in individuals with rare disorders, ranging from 41.64kB to 134.05Mb, arise de novo.

Conclusions: CNTN5 CNVs contribute to an individual’s overall risk for autism. Such variants with intermediate frequency and penetrance reveal part of the underlying genetic architecture of ASD that has been largely unexplored. By studying these intermediate variants, the total genetic profile of individuals with ASD can be better understood, leading to improved genetic diagnostic techniques and future therapeutics.