Vasculitis
Gene: NOTCH3
Pre-print
Review of research and diagnostic databases and literature review found 50 individuals from 31 families with biallelic variants.
13 PTCS (including splice) and 15 missense resulting in gain or loss of Cys residue.
AR PTCs are associated with early onset leukoencephalopathy including cognitive decline, dev delay/ID and dysmorphism
AR missense are associated with later onset (compared to AR PTVs) CADASIL-like phenotype. Similar severity and variability as AD CADASIL, difference is age of onset. Mid-adulthood for AD and early-adulthood for ARCreated: 30 Apr 2024, 4:57 a.m. | Last Modified: 30 Apr 2024, 4:57 a.m.
Panel Version: 0.80
Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes
neurodevelopmental disorder MONDO:0700092, NOTCH3-related; Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 MIM#125310
Variants in this GENE are reported as part of current diagnostic practice
Well established gene-disease association. Note recent publication 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, 11:29 p.m. | Last Modified: 1 Sep 2020, 11:29 p.m.
Panel Version: 0.23
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 125310
Publications
Phenotypes for gene: NOTCH3 were changed from Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 125310 to neurodevelopmental disorder MONDO:0700092, NOTCH3-related; Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 MIM#125310
Mode of inheritance for gene: NOTCH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Gene: notch3 has been classified as Green List (High Evidence).
Phenotypes for gene: NOTCH3 were changed from to Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 125310
Publications for gene: NOTCH3 were set to
Mode of inheritance for gene: NOTCH3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
gene: NOTCH3 was added gene: NOTCH3 was added to Vasculitis_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: NOTCH3 was set to Unknown