ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000003.11) (NC_000003.12)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
15106122 Fernandez et al (2004) reported a de novo balanced translocation involving chromosomes 3 and 10 with breakpoint in chromosome 3p that disrupts the 5' UTR of contactin 4 (CNTN4) in a patient with developmental delay and characteristic physical features of the distal 3p deletion syndrome [MIM: 613792]. The authors suggested that disruption of a single copy of CNTN4 is sufficient to confer clinical features of the 3p deletion syndrome phenotype, including developmental delay.
18349135 Roohi et al (2009) identified CNTN4 disruptions via an intragenic deletion (~654 kb, involving exons 2-6 of 25) in two siblings and an intragenic duplication (~791 kb, involving exons 1-5 of 25) in another unrelated individual with autism spectrum disorder (ASD) using whole genome array comparative genomic hybridization (aCGH). However, none of these individuals with intragenic copy number variations (CNVs) of CNTN4 demonstrated the classical distal 3p deletion syndrome phenotype. Of note, in this study, CNVs disrupting CNTN4 were all inherited from fathers without a history of ASD. In addition, a third affected sibling with ASD in the family with intragenic deletion did not carry the deletion. Further molecular characterization of the CNVs revealed that they resulted from Alu Y mediated unequal recombination. The authors stated that there have been a few rare reports of CNVs affecting CNTN4 in normal individuals as well (Database of Genomic Variants, Therefore, they offered incomplete penetrance of disruption of the gene.
21308999 Cottrell et al (2011) reported a deletion at 3p26.3 encompassing the 5? end of CNTN4 (~535 kb) in an individual with autism using array comparative genome hybridization (aCGH). This deletion was inherited from a phenotypically normal mother. Further, they sequenced CNTN4 in a cohort of 75 individuals with autism spectrum disorder (ASD) and 107 controls. Unique and evolutionary conserved nonsynonymous missense variants were identified in 4/75 unrelated individuals with an ASD, as well as in 1/107 controls. However, these data did not reach statistical significance, nor did the variants segregate with disease within all of the ASD families. The authors did not detect any difference in binding efficiencies of the murine CNTN4Ig1-4 fragments containing conserved variants found in two ASD families at amino acid positions 178 or 221.

Haploinsufficiency phenotype comments:

Currently, CNTN4 is not associated with an OMIM phenotype. The literature suggests that disruptions of a single copy of CNTN4 may play a role in a pathogenic mechanism for this gene. Disruptions of CNTN4 via chromosomal rearrangements, copy number variations, and missense mutations have been reported in individuals with various neurodevelopmental disorders, including autism spectrum disorder. However, given copy number deletion of this gene has been observed in the general population as noted in the Database of Genomic Variants (DGV) and due to parental inheritance and a weak evidence of family segregation with clinical phenotype, the clinical significance of CNTN4 haploinsufficiency remains uncertain. Additionally, in a study comparing a large cohort of children with ID and/or DD to unaffected adult controls, the incidence of observed deletions of CNTN4 was 15/15,767 in cases vs. 4/8,329 controls, which failed to reach statistical significance with a p value of 0.159 (PMID:21841781)

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity
Evidence for gain of function phenotype
PubMed ID Description
22750301 Guo et al (2012) identified large duplications involving CNTN4 in two individuals with autism using Illumina HumanCNV370-Quad BeadChip . The 2.4 Mb gain interval encompassed several other genes; however, 1.6 Mb gain disrupted only CNTN4 and CNTN6.

Triplosensitivity phenotype comment:

At this time there is no evidence that supports the triplosensitivity of CNTN4. Of note, In a study comparing a large cohort of children with ID and/or DD to unaffected adult controls, the incidence of observed gains of CNTN4 was 15/15,767 cases vs 17/8,329 controls (PMID:21841781)