CNTN6 – Tourette Syndrome

Tourette syndrome (TS) is a highly heritable neuropsychiatric disorder characterized by motor and vocal tics. A genome-wide case–control study of 2,434 TS cases and 4,093 matched controls found a significant enrichment of rare CNTN6 duplications conferring increased TS risk (OR = 10.1; P < 5×10⁻⁸), accounting for approximately 1% of TS cases ([PMID:28641109]).

Genetic analysis revealed that these CNTN6 duplications occur as large, singleton copy-number variants in heterozygous state, consistent with an autosomal dominant mechanism. Approximately 24 probands harbor such duplications, with no reported familial segregation data to date ([PMID:28641109]).

Functional studies in Cntn6-deficient (NB-3 knock-out) mice demonstrated significant impairments in motor coordination and equilibrium, as assessed by rotorod, wire-hang, and rod-walking tests, mirroring the motor dysfunction seen in TS ([PMID:12884264]). These findings support a dosage-sensitive role for CNTN6 in cortico-striato-thalamo-cortical circuit development and maintenance.

No conflicting or refuting reports have been described, although variable penetrance and phenotype expressivity warrant further investigation in independent cohorts and familial studies.

In summary, heterozygous CNTN6 duplications represent a moderate‐strength risk factor for Tourette syndrome, supported by robust statistical association and concordant in vivo functional data. Screening for CNTN6 CNVs may inform diagnostic evaluation and enhance understanding of TS pathogenesis.

References

• Neuron • 2017 • Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome. PMID:28641109
• Journal of neurobiology • 2003 • Impaired motor coordination in mice lacking neural recognition molecule NB-3 of the contactin/F3 subgroup. PMID:12884264

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