Submission Details

Variants involving CNTN6 have been reported in individuals with varying neurodevelopmental presentations (intellectual disability, autism spectrum disorder, ADHD, developmental delay), neuropsychiatric disorders (schizophrenia, bipolar disorder, depression), hypotonia, seizures, cardiac anomalies, low weight, microcephaly and dysmorphic features as early as 2014 (PMIDs: 25606055, 26257835, 27166760, 30508811). To date, all reported variants have been copy number changes; no individuals with presumed protein-altering single nucleotide variants in CNTN6 and demonstrable phenotypes have been reported.

The observed copy number changes include both multigenic events (deletions and duplications involving CNTN6 in addition to other genes), as well as deletions involving CNTN6 alone. The multigenic events are not counted as evidence in this evaluation as the role of the other genes in the presenting phenotype cannot be excluded. Single gene and intragenic deletions reported to date have been inherited from both affected and reportedly unaffected parents. In some cases, additional copy number variants were also observed. Additionally, CNTN6 is not constrained for loss-of-function variants (pLI = 0, gnomAD v2.1.1) and CNTN6 variants are seen at high enough frequencies in the non-affected population that it is difficult to assess the potential pathogenicity of these variants. For these reasons, all cases have been scored at 0. Although some authors have suggested that variants in CNTN6 could be involved in neurodevelopmental disorders with reduced penetrance, more information is needed to determine the role of CNTN6 in disease.

In summary, there is limited evidence to support the relationship between CNTN6 and complex neurodevelopmental disorder and the final classification is disputed. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on September 20, 2022 (SOP9).