ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000020.10) (NC_000020.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
17675531 Heron et al. (2007): Describes 3 intragenic deletions (all removing multiple continuous exons) of KCNQ2 detected amongst families affected with benign familial neonatal seizures (BFNS). An intragenic duplication of exons 3-12 was also described. These mutations were also detected in all affected relatives of each proband.
14534157 Singh et al. (2003): Describes a deletion extending from intron 8 of KCNQ2 through 22.1 kb past the KCNQ2 stop codon, deleting the last nine exons of KCNQ2. The authors propose that the "likely disease?causing mechanism is haploinsufficiency of the KCNQ2 protein, because mRNA produced from the deleted KCNQ2 allele lacks the poly A tail and is potentially degraded rapidly." Also describe 4 additional nonsense mutations detected in individuals with BFNS. The authors state that "these mutations cause a variable loss of function, and selective effects on the biophysical properties of KCNQ2/KCNQ3 heteromultimeric channels." Of note, this paper also describes "the first dominant negative mutation in KCNQ2 that has a phenotype of neonatal seizures without permanent clinical CNS impairment" (867insGGGCC).

Haploinsufficiency phenotype comments:

From Singh et al. (2003) (PMID:14534157): "Expression of a few of the mutations identified to date suggests that a partial loss of function in potassium current is sufficient to produce an epilepsy phenotype, and dominant negative mutations in either KCNQ2 or KCNQ3 may lead to a more severe phenotype (Jentsch, 2000, PMID:11252765)

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