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CNTN4 – Autism Spectrum Disorder

Rare copy-number variants disrupting CNTN4 have been reported in individuals with autism spectrum disorder. Array-based CGH identified a paternally inherited deletion in two siblings and a duplication in a third unrelated case, with Alu Y–mediated breakpoints interrupting CNTN4 (PMID:18349135). Subsequent screening of three unrelated families revealed one additional deletion and two duplications within CNTN4, all paternally derived and associated with ASD, cognitive delay, motor delay (HP:0001270), and speech impairment, demonstrating variable expressivity and incomplete penetrance (PMID:31422286). No recurrent coding variants have been described.

Genome-wide studies in East Asian and European cohorts provided nominal association signals for CNTN4 in case-control and family-based analyses, but these did not reach genome-wide significance and lacked replication across populations (PMID:26314684; PMID:19404257). Segregation is limited to two affected siblings in one family, and other familial CNVs do not co-segregate consistently. Contactin 4 is a neuronal cell-adhesion molecule critical for synaptic network formation and plasticity, offering biological plausibility for ASD when disrupted, yet direct functional assays of CNTN4 variants in ASD models are lacking (PMID:18349135).

Key Take-home: Rare CNTN4 CNVs and nominal association signals support a limited role for CNTN4 in ASD risk, warranting further genetic and functional investigation.

References

  • Journal of medical genetics • 2009 • Disruption of contactin 4 in three subjects with autism spectrum disorder. PMID:18349135
  • European journal of medical genetics • 2020 • Intragenic CNTN4 copy number variants associated with a spectrum of neurobehavioral phenotypes. PMID:31422286
  • Autism research • 2016 • Genome-wide Association Study of Autism Spectrum Disorder in the East Asian Populations. PMID:26314684
  • Nature • 2009 • Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. PMID:19404257

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

CNVs in 6 probands across two case series (PMID:18349135; PMID:31422286) and nominal association in GWAS (PMID:26314684; PMID:19404257) but lacking consistent segregation and replication

Genetic Evidence

Limited

Multiple rare CNTN4 CNVs in unrelated ASD cases (total n=6) and nominal association signals in population studies

Functional Evidence

Limited

CNTN4’s role in neuronal network formation is biologically plausible for ASD but direct functional assays of ASD-associated variants are lacking