Early onset or syndromic epilepsy

Gene: TMEM63B

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.

Created: 2 May 2024, 1:13 p.m. | Last Modified: 6 May 2024, 9:25 p.m.

Panel Version: 5.6

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

We identify de novo missense/inframe variants of TMEM63B in 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes. The Val44Met variant was recurrent in 7/17 individuals.
Our observations argue against haploinsufficiency being the obvious pathogenic mechanism in our cohort. In-vitro modelling in Neuro2a cells of 6/10 distinct variants we identified (p.Val44Met, p.Arg433His, p.Thr481Asn, p.Gly580Ser, p.Arg660Thr, and p.Phe697Leu), each affecting a distinct transmembrane domain of the channel, demonstrated inward leak cation currents across the mutated channel even in isotonic conditions, suggesting a gain of function, although the response to hypo-osmotic challenge was impaired, as were the Ca2+ transients generated under hypo-osmotic stimulation.

Created: 10 Aug 2023, 9:57 a.m. | Last Modified: 10 Aug 2023, 9:57 a.m.

Panel Version: 4.84

Phenotypes
abnormal myelination; developmental and epileptic encephalopathy; hemolytic anemia; infantile spasms

Publications

• 37421948

Green List (high evidence)

Comment on list classification: There is sufficient evidence available (17 unrelated cases) in support of promoting this gene to green rating in the next GMS review.

Created: 28 Jul 2023, 6:37 p.m. | Last Modified: 28 Jul 2023, 6:38 p.m.

Panel Version: 4.72

PMID:37421948 - 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame. All individuals had early-onset drug-resistant epilepsy, whose onset ranged from birth to 3 years but occurred within the first year in 14/17 (82%) and in the first month of life in 6/17 (35%).
Sources: Literature

Created: 28 Jul 2023, 6:32 p.m. | Last Modified: 28 Jul 2023, 6:37 p.m.

Panel Version: 4.71

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
developmental and epileptic encephalopathy, MONDO:0100062

Publications

• 37421948