CNTN4

Inheritance Pattern: AD

Disease ID:MONDO:0005258

Submitter: Illumina

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*CNTN4* encodes the neuronal cell adhesion molecule contactin 4. The relationship between *CNTN4* variants and neurodevelopmental disorders was first suggested in 2004, when Fernandez et al. reported a *de novo* balanced 3p26;10q26 translocation disrupting *CNTN4* in a boy with developmental delay and autism (PMID: 15106122). This translocation was not used as evidence because the contribution of other genes cannot be ruled out. Subsequent publications reported *CNTN4* variants, mainly copy number variants (CNVs), in individuals with autism, intellectual disability, delayed speech and motor development, seizures, and hypotonia (PMIDs: 21308999, 21658581, 24768552, 31422286). Due to the variable phenotypic spectrum, variants in *CNTN4* have been curated under the disease entity complex neurodevelopmental disorder. *CNTN4* CNVs have also been reported in attention deficit hyperactivity disorder; these CNVs were not included in this curation. Ten CNVs (three deletions and seven duplications involving only *CNTN4*), five missense variants, and one splice variant reported in 16 probands in seven publications (PMIDs: 21308999, 21658581, 24768552, 28714951, 29271092, 31422286; doi: [10.1016/j.rasd.2024.102399](https://doi.org/10.1016/j.rasd.2024.102399)) are included in this curation. Many of the reported variants were inherited from unaffected parents and/or were present at high frequencies in gnomAD. Five individuals with autism spectrum disorder and intragenic duplications of *CNTN4* ranging from 56 to 300 kb were reported by Al-Mamari et al. (2024, doi: [10.1016/j.rasd.2024.102399](https://doi.org/10.1016/j.rasd.2024.102399)); three duplications were *de novo*, while two were inherited from unaffected fathers. Since this report does not have a PMID, it cannot formally be documented in the curation at this time. Multiple other deletions and duplications involving *CNTN4* have been reported in large autism cohorts, but were not counted as evidence because they either overlapped multiple genes, were intronic, or overlapped only non-coding exons (e.g., PMIDs: 21658581, 24768552). Of note, *CNTN4* is not constrained for either loss-of-function variants (pLI = 0, gnomAD v4.1.0) or missense variants (Z = 0.64). Accordingly, a large case-control study investigating CNVs failed to find statistical evidence that *CNTN4* deletions were more frequent in children with intellectual disability compared to controls (PMID: 21841781). Since there is no convincing evidence that heterozygous *CNTN4* variants cause disease, all cases in this curation were scored 0. Although some authors have suggested that variants in *CNTN4* could be involved in neurodevelopmental disorders with reduced penetrance, more information is needed to delineate this. Experimental evidence from knockout mouse models suggesting that disruption of *Cntn4* alters hippocampal synaptic plasticity and the dendritic arborization and spine density of pyramidal neurons (PMIDs: 33542194, 38745463) was not scored, given the lack of convincing genetic evidence. In summary, the evidence supporting the relationship between *CNTN4* and autosomal dominant complex neurodevelopmental disorder has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *CNTN4* plays in this disease. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 14, 2022 (SOP 9). It was reevaluated on August 7, 2024 (SOP 10). As a result of this reevaluation, the classification changed from Limited to Disputed due to a lack of convincing genetic evidence towards this gene-disease relationship.