Familial cerebral small vessel disease

Gene: NOTCH3

Comment when marking as ready: Tier 1 gene in BRIDGE Study. Associated with this phenotype in G2P
This gene is included in the exclusion criteria for this panel

Created: 1 Jul 2016, 4:31 p.m.

Green List (high evidence)

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is caused by mutations in the NOTCH3 gene.

Cysteine-changing mutations in the epidermal growth factor-like repeat (EGFR) domains throughout exons 2- 24 are known to cause CADASIL. These mutations are believed to result in the accumulation of the NOTCH3 ectodomain around smooth muscle cells in the small vessels.

Loss-of-function mutations are not known to be associated with CADASIL. NOTCH3 mutations that do not alter the number of cysteine residues in the EGFR domains have not been proven to be associated with CADASIL.

It is recommended that all exons 2-24 are screened for cysteine-changing mutations. Where non-cysteine changing mutations are detected, the diagnosis of CADASIL should be questioned, and can be clinically confirmed with skin biopsy (to demonstrate Granular Osmiophilic Material on electron microscopy), and by segregation analysis in the family. Alternative genetic diagnoses should also be considered in this context.

Created: 22 Jun 2016, 3:06 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Migraine; Encephalopathy; Stroke; Cognitive impairment; Dementia; Seizures;

Publications

• PMID: 8878478
• 19528524

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Comment on list classification: Variants in OMIM and ClinVar

Created: 10 May 2016, 2:01 p.m.

Phenotypes and mode of inheritance from OMIM.

Created: 11 Jan 2016, 9:46 a.m.