Familial cerebral small vessel disease

Gene: NOTCH3

Green List (high evidence)

NOTCH3 (notch 3)
EnsemblGeneIds (GRCh38): ENSG00000074181
EnsemblGeneIds (GRCh37): ENSG00000074181
OMIM: 600276, Gene2Phenotype
NOTCH3 is in 11 panels

4 reviews

Sarah Leigh (Genomics England Curator)

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.

Rhea Tan (University of Cambridge)

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

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

Caroline Wright (Genomics England Curator)

Comment on list classification: Variants in OMIM and ClinVar
Created: 10 May 2016, 2:01 p.m.

Ellen McDonagh (Genomics England Curator)

Phenotypes and mode of inheritance from OMIM.
Created: 11 Jan 2016, 9:46 a.m.

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert list
  • Expert Review Green
  • UKGTN
  • Eligibility statement prior genetic testing
  • Other
Phenotypes
  • Migraine
  • Encephalopathy
  • Stroke
  • Cognitive impairment
  • Dementia
  • Seizures
  • Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 125310
OMIM
600276
Clinvar variants
Variants in NOTCH3
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

4 Jul 2016, Gel status: 4

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for NOTCH3 were set to Migraine; Encephalopathy; Stroke; Cognitive impairment; Dementia; Seizures; Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 125310

1 Jul 2016, Gel status: 4

Upload gene information

Sarah Leigh (Genomics England Curator)

NOTCH3 was added to Familial cerebral small vessel diseasepanel. Sources: Expert list

1 Jul 2016, Gel status: 4

Gene classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

1 Jul 2016, Gel status: 4

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for NOTCH3 were set to Migraine; Encephalopathy; Stroke; Cognitive impairment; Dementia; Seizures; Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1125310

1 Jul 2016, Gel status: 4

Set publications

Sarah Leigh (Genomics England Curator)

Publications for NOTCH3 were set to 12754354; 8878478; 19528524; http://www.cambridgestroke.com/genetictesting.php

10 May 2016, Gel status: 4

Set publications

Caroline Wright (Genomics England Curator)

Publications for NOTCH3 were set to 12754354; 8878478; http://www.cambridgestroke.com/genetictesting.php

10 May 2016, Gel status: 4

Set publications

Caroline Wright (Genomics England Curator)

Publications for NOTCH3 were set to 12754354; 8878478 http://www.cambridgestroke.com/genetictesting.php

10 May 2016, Gel status: 4

Set publications

Caroline Wright (Genomics England Curator)

Publications for NOTCH3 were set to 12754354;8878478

10 May 2016, Gel status: 4

Gene classified by Genomics England curator

Caroline Wright (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

11 Jan 2016, Gel status: 1

Upload gene information

Ellen McDonagh (Genomics England Curator)

NOTCH3 was added to Familial cerebral small vessel diseasepanel. Sources: UKGTN

11 Jan 2016, Gel status: 0

Added New Source

Ellen McDonagh (Genomics England Curator)

NOTCH3 was added to Familial cerebral small vessel diseasepanel. Sources: Eligibility statement prior genetic testing,Other

11 Jan 2016, Gel status: 0

Created

Ellen McDonagh (Genomics England Curator)

NOTCH3 was created by ellenmcdonagh