CADASIL

Gene: NOTCH3

Green List (high evidence)

Comment on mode of inheritance: Both monoallelic and biallelic variants (cysteine-involving missense variants) are known to cause CADASIL spectrum phenotype. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.

Created: 9 Jun 2026, 1:57 p.m. | Last Modified: 9 Jun 2026, 1:57 p.m.

Panel Version: 1.7

Review by Achchuthan Shanmugasundram (Genomics England Curator), copied from Adult onset leukodystrophy:

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.

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.

Confluent deep, subcortical white matter lesions were reported in 21 patients with biallelic cysteine-involving missense variants. In addition, white matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL.

Created: 9 Jun 2026, 1:55 p.m. | Last Modified: 9 Jun 2026, 1:55 p.m.

Panel Version: 1.7

Comment on phenotypes: OMIM phenotype updated 9th June 2026.

Created: 9 Jun 2026, 1:15 p.m. | Last Modified: 9 Jun 2026, 1:15 p.m.

Panel Version: 1.7

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, OMIM:621295; Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310; cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, MONDO:0000914

Publications

• 39191170

Green List (high evidence)

Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #125310) and the OMIM record was last accessed on 17 December 2025.

Created: 17 Dec 2025, 10:13 p.m. | Last Modified: 17 Dec 2025, 10:13 p.m.

Panel Version: 1.5

NOTCH3 has been added to the panel for R337 CADASIL with a green rating as agreed with the NHS Genomic Medicine Service.

Created: 30 Jun 2023, 9:38 a.m. | Last Modified: 30 Jun 2023, 9:38 a.m.

Panel Version: 0.1

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted