Print Email Facebook Twitter Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank Title Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank: CADASIL to nonpenetrance Author Rutten, Julie W. (Leiden University Medical Center) Hack, Remco J. (Leiden University Medical Center) Duering, Marco (Ludwig Maximilians University) Gravesteijn, Gido (Universiteit Leiden) Dauwerse, Johannes G. (Leiden University Medical Center) Overzier, Maurice (Universiteit Leiden) van den Akker, E.B. (TU Delft Pattern Recognition and Bioinformatics) Slagboom, Eline (Universiteit Leiden) Holstege, H. (TU Delft Intelligent Systems) Department Intelligent Systems Date 2020 Abstract To 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. The exome and genome sequencing datasets of the UK Biobank (n = 50,000) and cohorts of cognitively healthy elderly (n = 751) were queried for cysteine-altering NOTCH3 variants. Brain MRIs of individuals harboring such variants were scored according to Standards for Reporting Vascular Changes on Neuroimaging criteria, and clinical information was extracted with ICD-10 codes. Clinical and neuroimaging data were compared to age- and sex-matched UK Biobank controls and clinically diagnosed patients from the Dutch cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) registry. We identified 108 individuals harboring a cysteine-altering NOTCH3 variant (2.2 of 1,000), of whom 75% have a variant that has previously been reported in CADASIL pedigrees. Almost all variants were located in 1 of the NOTCH3 protein epidermal growth factor-like repeat domains 7 to 34. White matter hyperintensity lesion load was higher in individuals with NOTCH3 variants than in controls (p = 0.006) but lower than in patients with CADASIL 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 years. There was no increased risk of stroke. Although 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 years. This shows that NOTCH3 cysteine altering variants are associated with an extremely broad phenotypic spectrum, ranging from CADASIL to nonpenetrance. To reference this document use: http://resolver.tudelft.nl/uuid:dea5bf07-4bec-4d5e-98a9-1674411409bc DOI https://doi.org/10.1212/WNL.0000000000010525 ISSN 0028-3878 Source Neurology, 95 (13), e1835-e1843 Part of collection Institutional Repository Document type journal article Rights © 2020 Julie W. Rutten, Remco J. Hack, Marco Duering, Gido Gravesteijn, Johannes G. Dauwerse, Maurice Overzier, E.B. van den Akker, Eline Slagboom, H. Holstege, More Authors Files PDF e1835.full.pdf 652.07 KB Close viewer /islandora/object/uuid:dea5bf07-4bec-4d5e-98a9-1674411409bc/datastream/OBJ/view