Early-onset Dementia

Gene: NOTCH3

Green List (high evidence)

Pre-print
Review of research and diagnostic databases and literature review found 50 individuals from 31 families with biallelic variants.

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 AR

Created: 30 Apr 2024, 5:55 a.m. | Last Modified: 30 Apr 2024, 5:55 a.m.

Panel Version: 1.14

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 MIM#125310

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

Green List (high evidence)

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, 11:24 p.m. | Last Modified: 1 Sep 2020, 11:24 p.m.

Panel Version: 0.73

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 125310

Publications

• 31960911