ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 7q35-q36.1
  • GRCh37/hg19 chr7: 145,813,453-148,118,090
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr7: 146,116,207-148,420,998
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000007.13) (NC_000007.14)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
22031302 Mikhail et al., 2011 reports an intragenic deletion in CNTNAP2 in a patient with intellectual disability (ID)/developmental delay (DD), etc., but the inheritance of the variant could not be determined.

Haploinsufficiency phenotype comments:

PLEASE NOTE: Biallelic mutation of CNTNAP2 is associated with cortical dysplasia-focal epilepsy syndrome observed in the Old Order Amish population and a Pitt-Hopkins-Like Syndrome (MIM #610042). PMID 27439707: See Smogavec et al., 2016 for a review of the literature and reports on the mutation and phenotypic spectrum of 8 individuals from 6 unrelated families with bi-allelic variants in CNTNAP2, all of whom had ID and epilepsy disorders. Heterozygous copy number changes and missense mutations in CNTNAP2 have been reported in association with numerous phenotypes, including intellectual disability, epilepsy, schizophrenia, Gilles de la Tourette syndrome, and increased susceptibility to autism. However, due to the presence of additional chromosomal imbalances or potentially pathogenic variants within many cases and/or demonstrated inheritance of the aberration from an apparently unaffected parent, and the finding of deletions of exonic sequence of CNTNAP2 in control populations (3 in the control vs 4 in the patient population in Cooper et al. 2011), the potential haploinsufficiency for CNTNAP2 is not certain at this time. PMID 21448237: Nord et al. 2011 study reported a patient with autism who had a deletion of the CNTNAP2 promoter region. Expression studies in transformed lymphoblasts demonstrated that the patient had less CNTNAP2 expression than his transmitting mother who has less expression than his normal father. The other CNTNAP2 allele was not sequenced to look for additional mutations that could potentially explain the decrease in CNTNAP2 expression in the proband. PMID 21827697: See Gregor et al., 2011 for recent review of literature, including a report of 7 probands with intellectual disability and heterozygous mutations (splice-site, frameshift, nonsense or intragenic deletions) in CNTNAP2. In this study, five mutations were inherited from a healthy parent, one patient with de novo deletion had additional chromosomal imbalances, and inheritance for last patient was not determined PMID 25621974: Murdoch et al., 2015. This large case-control study found no evidence for a significant association of heterozygous SNPs in CNTNAP2 with ASD, this was in contrast to a previous study by the same lab (PMID: 18179895, Bakkaloglu et al., 2007) that reported a significant association with the heterozygous presence of the I869T variant, which has since been reclassified by SIFT as benign. Murdoch et al. report that in an expanded dataset they no longer found a significant association of the I869T variant in the case group. Moreover they determined the transmission of every rare/singleton mutation seen in the probands, and found no confirmed de novo mutations in CNTNAP2. PMID 30586385: Toma et al., 2018, this study did a gene-based association and did not find a significant association of heterozygous SNPs in CNTNAP2 with psychiatric phenotypes, including previously associated SNPs; rs7794745 and rs2710102. This study also compared the genomic location and size of CNV deletions in CNTNAP2 reported in the literature for individuals with psychiatric disorders, they detected no difference in the distribution of the case structural variants with structural variants present in control populations. Finally they reported on a family with 5 relatives affected with Bipolar I disorder where the proband had a 131 kb deletion in intron 1 of the gene, this deletion variant did not segregate with disease status in the family.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity