White matter disorders and cerebral calcification - narrow panel

Gene: NOTCH3

Green List (high evidence)

Comment on list classification: As reviewed by Lauren Turton, there is sufficient evidence available for the association of biallelic LoF variants from NOTCH3 gene with childhood-onset leukoencephalopathy. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 1 Jul 2025, 6:17 p.m. | Last Modified: 1 Jul 2025, 6:17 p.m.

Panel Version: 7.8

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.

18 patients with LoF variants typically displayed early-onset leukoencephalopathy with significant periatrial white matter volume loss. Mean age at the onset of symptoms was 28 months, ranging from congenital to 17 years old.

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.

Created: 1 Jul 2025, 6:12 p.m. | Last Modified: 1 Jul 2025, 6:12 p.m.

Panel Version: 7.4

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
neurodevelopmental disorder, MONDO:0700092; leukodystrophy, MONDO:0019046

Publications

• 39191170

Green List (high evidence)

Twenty-five patients from 17 unrelated families harbouring homozygous or compound heterozygous variants in NOTCH3. Among them 18 carried LoF variants.
Patients had a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Mean age at the onset of symptoms was 28 months, ranging from congenital to 17 years old.
Showed that patients with the biallelic LoF variants had a different phenotype to that seen in CADASIL.

Created: 4 Jun 2025, 2:14 p.m. | Last Modified: 4 Jun 2025, 2:14 p.m.

Panel Version: 7.2

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spasticity, stroke, periatrial white matter volume loss

Publications

• 39191170