Submission Details

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) 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); 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.

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) 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); 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, gnomAD v4.1.0). 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.