Broad phenotype of cysteine altering NOTCH3 variants in UK Biobank: CADASIL to non-penetrance

• Published in: Neurology
• Main Authors: Rutten, Julie W, Hack, Remco J, Duering, Marco, Gravesteijn, Gido G, Dauwerse, Johannes G, Overzier, Maurice, van den Akker, Erik B, Slagboom, Eline, Holstege, Henne, Nho, Kwangsik, Saykin, Andrew, Dichgans, Martin, Malik, Rainer, Lesnik Oberstein, Saskia A.J
• Format: Journal Article
• Language: English
• Published: American Academy of Neurology 29-07-2020
• ISSN: 0028-3878; 1526-632X
• DOI: 10.1212/WNL.0000000000010525

OBJECTIVETo determine the small vessel disease spectrum associated with cysteine altering NOTCH3 variants in community dwelling individuals, by analyzing the clinical and neuroimaging features of UK Biobank participants harboring such variants.
METHODSThe exome- and genome sequencing datasets of UK Biobank (n=50,000) and cohorts of cognitively healthy elderly (n=751) were queried for cysteine altering NOTCH3 variants. Brain MRI’s of individuals harboring such variants were scored according to STRIVE criteria and clinical information was extracted using ICD-10 codes. Clinical and neuroimaging data were compared to age- and sex matched UK Biobank controls and clinically diagnosed patients from the Dutch CADASIL registry.
RESULTSWe identified 108 individuals harboring a cysteine altering NOTCH3 variant (2.2/1000), of which 75% has a variant which has been previously reported in CADASIL pedigrees. Almost all variants were located in one of the NOTCH3 protein epidermal growth factor-like repeat domains 7-34. White matter hyperintensity lesion load was higher in individuals with NOTCH3 variants than in controls (p=0.006), but lower than in CADASIL patients with the same variants (p<0.001). Almost half of the 24 individuals with brain MRI had a Fazekas score of 0 or 1 up to age 70. There was no increased risk of stroke.
CONCLUSIONSAlthough community dwelling individuals harboring a cysteine altering NOTCH3 variant have a higher small vessel disease MRI burden than controls, almost half have no MRI abnormalities up to age 70. This shows that NOTCH3 cysteine altering variants are associated with an extremely broad phenotypic spectrum, ranging from CADASIL to non-penetrance.