Early onset or syndromic epilepsy

Gene: KCNK4

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

Not listed on OMIM in assocation with disease. HGMD Pro - Bauer et al, 2018 - 2 unrelated subjects with facial dysmorphism, hypertrichosis, EEG anomalies/epilepsy, variable dev delay, gingivial overgrowth. Two variants identifed in each individual both missense - arose de novo. A third patient was also identified with a similar phenotype - same mutation as patient 1 also de novo. Patch clamp experiments suggest GOF.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 30290154

Comment on list classification: Based on evidence in the literature and from external review, Sarah Leigh on 16 Oct 2018 classified gene: KCNK4 as Green List (high evidence) on Genetic Epilepsy Syndromes panel v0.504. However, due to a data outage in PanelApp at the time, the rating of this particular gene on this panel was not updated eg: the rating of a gene was changed, but was not reflected in production however action was logged in the activity. Issue has now been solved so the rating of this gene is now being changed to Green, as the change will now be reflected in production to represent the required update on Genetic Epilepsy Syndromes panel v0.510

Created: 31 Oct 2018, 2:04 p.m.

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: Expert Review, Literature

Created: 11 Oct 2018, 5:51 p.m.

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

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

Publications

• 30290154

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