Adult onset neurodegenerative disorder

Gene: NOTCH3

PMID: 31960911 - Gravesteijn et al 2020 - describe a family with a unique cysteine-altering NOTCH3 variant in exon 9 in 5 individuals, which is predicted to cause natural exon 9 skipping. This mimics the therapeutic NOTCH3 cysteine correction approach and allows the effect of cysteine corrective exon skipping on NOTCH3 protein aggregation and disease severity in humans to be studied. In this family the CADASIL phenotype was mild.

Created: 1 Sep 2020, 3:49 p.m. | Last Modified: 1 Sep 2020, 3:49 p.m.

Panel Version: 2.14

Publications

• 31960911

I don't know

Hereditary multi-infarct dementia in multiple members of families in a pattern consistent with autosomal dominant inheritance was reported by Sourander and Walinder (1977) and Sonninen and Savontaus (1987). The disorder is characterized by relapsing strokes with neuropsychiatric symptoms and affects relatively young adults of both sexes. Not clear from HGMDPro that this disease association is confirmed (variants are amber-rated) - majority of variants are associated with CADASIL: amber/red?

Created: 2 Sep 2019, 4:06 p.m. | Last Modified: 2 Sep 2019, 4:06 p.m.

Panel Version: 1.99

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Dementia

Green List (high evidence)

Adult onset (third decade)

Created: 23 Jul 2019, 3:35 p.m. | Last Modified: 23 Jul 2019, 3:35 p.m.

Panel Version: 1.72

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Dementia

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

As discussed with the GMS Neurology Specialist Test Group webex call11th September 2019 : The Specialist Test Group all agreed that there is enough evidence to rate this gene Green

Created: 20 Sep 2019, 4:19 p.m. | Last Modified: 20 Sep 2019, 4:19 p.m.

Panel Version: 1.106

Review and rating from Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group. All the green and amber, except for the genes with triplet repeats, were reviewed.

Created: 2 Sep 2019, 4:46 p.m. | Last Modified: 2 Sep 2019, 4:46 p.m.

Panel Version: 1.101

Review and rating submitted by Nick Beauchamp (Sheffield Diagnostic genetics Service), on behalf of Yorkshire and North East GLH for GMS Neurology specialist test group.

Created: 23 Jul 2019, 3:51 p.m. | Last Modified: 23 Jul 2019, 3:51 p.m.

Panel Version: 1.74

Review and rating submitted byJames Polke (North Bristol NHS Trust), unless specified in the review comment, on behalf of London North GLH for GMS Neurology specialist test group.

Created: 23 Apr 2019, 5:35 p.m.

Green List (high evidence)

Variants in this GENE are reported as part of current diagnostic practice