CNTN4

Gene Facts

• HGNC Symbol: CNTN4 (HGNC:2174)
• HGNC Name: contactin 4
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: BIG-2
• %HI: 6.9
• pLI: 0
• LOEUF: 0.73
• Cytoband: 3p26.3-p26.2
• Genomic Coordinates:

  GRCh37/hg19:	chr3:2140550-3099643
  GRCh38/hg38:	chr3:2098866-3057959

• MANE Select Transcript: NM_175607.3 ENST00000418658.6
• Function: Contactins mediate cell surface interactions during nervous system development. Has some neurite outgrowth-promoting activity. May be involved in synaptogenesis. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-4891
• ClinGen Curation ID: CCID:006894
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: No Evidence for Haploinsufficiency (0)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 06/14/2022

Haploinsufficiency (HI) Score Details

• HI Score: 0
• HI Evidence Strength: No Evidence for Haploinsufficiency

HI Disease

• Complex Neurodevelopmental Disorder

HI Evidence

• PUBMED: 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. Fine mapping of this rearrangement demonstrates that the translocation breakpoint on chromosome 3 falls within the recently identified minimal candidate region for 3p deletion syndrome and disrupts the Contactin 4 (CNTN4) mRNA transcript at 3p26.2–3p26.3. The other translocation breakpoint in chromosome 10 lies within a gene-poor region in the band 10q26.11. No known or predicted transcripts or spliced ESTs were identified on these clones with the use of the UCSC genome browser. The same group further evaluated this patient in 2008 (Fernandez et al, 2008 PMID 18551756) using the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule-Generic (ADOS-G), as well as assessment of cognitive and adaptive functioning, revealed the patient's phenotype met the criteria for an ASD diagnosis.
• PUBMED: 18349135
  Roohi et al (2009) identified CNTN4 disruptions via an intragenic deletion (~654 kb, involving exons 2-6 of 25) in two siblings with ASD using aCGH. Of note, the CNTN4 deletions in the two siblings were inherited from their father without ASD phenotype. These two siblings has a third sibling with ASD, but without the same deletion. They also detected an intragenic duplication (~791 kb, involving exons 1-5 of 25 of CNTN4) in another unrelated individual with ASD. He also inherited this duplication from his father without ASD. None one of these individuals with intragenic CNVs of CNTN4 demonstrated the classical distal 3p deletion syndrome phenotype. 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 control population individuals as well (Database of Genomic Variants, http://projects.tcag.ca/variation/). Therefore, they suggested incomplete penetrance of disruption of the gene.
• PUBMED: 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.
• PUBMED: 31422286
  Zhang et al. (2020) performed clinical and genetic characterization of three individuals from unrelated families with copy number variants (CNV) (one deletion and two duplications) within CNTN4. The deletion in one patient was 0.31 Mb including the exon 8-12 of CNTN4. One duplication was 0.44 Mb including exon 1-3, another duplication was 0.49 Mb including exon 1-2 of CNTN4. The patients exhibited cognitive delay (3/3), growth restriction (3/3), motor delay (2/3), and febrile seizure/epilepsy (2/3). Parental studies for the proband with the deletion and one of the 2 probands with the duplication revealed paternal origin of the CNTN4 CNV.
• PUBMED: 19404257
  Glessner et al. (2009) performed a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 control children of European ancestry, to comprehensively identify CNVs conferring susceptibility to ASDs. They found 3 ASD patients with 733 bp (chr3: 1915190–1915922, Build36 UCSC genome browser) deletions in CNTN4, and 0 in controls. Also, there is one patient with a duplication in CNTN4, which was detected in one control as well. The inheritance information was not specified.
• PUBMED: 31801954
  D’Abate et al. (2009) described clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. One patient with ASD has a 1.8 Mb deletion encompassing part of the CNTN4 gene and part of the CNTN6 gene. Another patient with ASD has a 70 kb partial gene duplication of CNTN4.

• HI Evidence Comments: 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 (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: 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)