Early onset or syndromic epilepsy
Gene: TMEM63BWe 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
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: LiteratureCreated: 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
Gene: tmem63b has been classified as Amber List (Moderate Evidence).
Tag Q3_23_promote_green tag was added to gene: TMEM63B.
gene: TMEM63B was added gene: TMEM63B was added to Early onset or syndromic epilepsy. Sources: Literature Mode of inheritance for gene: TMEM63B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TMEM63B were set to 37421948 Phenotypes for gene: TMEM63B were set to developmental and epileptic encephalopathy, MONDO:0100062 Review for gene: TMEM63B was set to GREEN