Early onset or syndromic epilepsy

Gene: NOTCH3

Green List (high evidence)

Comment on list classification: There is sufficient evidence available for the association of biallelic LoF variants in NOTCH3 gene with epilepsy. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 1 Jul 2025, 4:43 p.m. | Last Modified: 1 Jul 2025, 4:43 p.m.

Panel Version: 8.7

PMID:39191170 reported a cohort of 50 patients with biallelic variants in NOTCH3 gene, which includes 25 previously unreported individuals from 17 families and 25 individuals already reported in published literature from 14 families.

Of these, 18 unreported individuals from 10 families and 8 already reported individuals from five families were identified with biallelic loss-of-functional variants. These 26 patients with biallelic LoF variants are reported with a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia.

Of these 24 patients from 15 families had developmental delay, ranging from mild or only motor delay in 7 patients to global developmental impairment in 17 patients. 21 patents from 13 families had predominantly severe intellectual disability, of which five had mild ID. Seizures were reported in 10 patients from seven different families.

Seven previously unreported cases from seven different families and 17 previously published cases from nine families were identified with biallelic cysteine-involving missense variants. These 24 patients fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss.

Biallelic variants in NOTCH3 are not yet associated with any phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature

Created: 1 Jul 2025, 4:37 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
neurodevelopmental disorder, MONDO:0700092

Publications

• 39191170