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Intellectual disability

Gene: KCNK4

Amber List (moderate evidence)

KCNK4 (potassium two pore domain channel subfamily K member 4)
EnsemblGeneIds (GRCh38): ENSG00000182450
EnsemblGeneIds (GRCh37): ENSG00000182450
OMIM: 605720, Gene2Phenotype
KCNK4 is in 3 panels

3 reviews

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Three unrelated individuals reported with a distinctive syndromic ID condition. As the variants are de novo, the fact that one of the variants was found in two of the individuals only adds weight to the evidence that the affected residue is functionally important.
Created: 8 Feb 2020, 9:24 a.m. | Last Modified: 8 Feb 2020, 9:24 a.m.
Panel Version: 3.0

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome 618381

Publications

Variants in this GENE are reported as part of current diagnostic practice

Ivone Leong (Genomics England Curator)

Comment on list classification: New gene added by external expert and reviewed by curation team. Given an amber rating as there is currently only one report detailing 3 unrelated patients (2 Italian and 1 of European ancestry) who have variants (2 patients have the same missense variant and the third patient has a different missense variant). The paper also describe some in vitro cell studies. KCNK4 is classified as a possible disease causing gene for FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth) on Gene2Phenotype.
Created: 14 Feb 2019, 2:51 p.m.

Konstantinos Varvagiannis (Other)

I don't know

PMID: 30290154 reports on 3 unrelated individuals with de novo missense KCNK4 variants. All three individuals presented with developmental delay and epilepsy. Severe intellectual disability was a feature in two of these individuals while the third displayed low average intellectual functioning (IQ of 85). Other features common in all included facial dysmorphism (bushy eyebrows, long eyelashes, thin everted upper lip, micrognathia), generalized hypertrichosis and gingival overgrowth.

The two missense variants reported [(p.Ala172Glu) and (p.Ala244Pro)] occurred as de novo events in all subjects, while the first SNV was observed in 2 (of the 3) patients with severe intellectual disability.

Functional studies were suggestive of a gain-of-function effect. In line with this mechanism, Kcnk4 knockout mice did not seem to exhibit seizures, deficits in cognition or other neurodevelopmental phenotypes in a study conducted earlier and cited by the authors (PMID: 15175651).

As a result this gene can be considered for inclusion in the panel as amber (or green).
Sources: Literature, Expert Review
Created: 11 Oct 2018, 5:49 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Neurodevelopmental delay; Intellectual disability; Seizures; Gingival overgrowth; Hypertrichosis

Publications

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
Phenotypes
  • Neurodevelopmental delay
  • Intellectual disability
  • Seizures
  • Gingival overgrowth
  • Hypertrichosis
OMIM
605720
Clinvar variants
Variants in KCNK4
Penetrance
unknown
Publications
Mode of Pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Panels with this gene

History Filter Activity

14 Feb 2019, Gel status: 2

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: kcnk4 has been classified as Amber List (Moderate Evidence).

11 Oct 2018, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance, Set mode of pathogenicity

Konstantinos Varvagiannis (Other)

gene: KCNK4 was added gene: KCNK4 was added to Intellectual disability. Sources: Literature,Expert Review Mode of inheritance for gene: KCNK4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: KCNK4 were set to 30290154 Phenotypes for gene: KCNK4 were set to Neurodevelopmental delay; Intellectual disability; Seizures; Gingival overgrowth; Hypertrichosis Penetrance for gene: KCNK4 were set to unknown Mode of pathogenicity for gene: KCNK4 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: KCNK4 was set to AMBER