Broad phenotype of cysteine-altering <i>NOTCH3</i> variants in UK Biobank

Abstract

<h3>Objective</h3> To determine the small vessel disease spectrum associated with cysteine-altering <i>NOTCH3</i> variants in community-dwelling individuals by analyzing the clinical and neuroimaging features of UK Biobank participants harboring such variants. <h3>Methods</h3> 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 <i>NOTCH3</i> 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. <h3>Results</h3> We identified 108 individuals harboring a cysteine-altering <i>NOTCH3</i> 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 <i>NOTCH3</i> variants than in controls (<i>p</i> = 0.006) but lower than in patients with CADASIL with the same variants (<i>p</i> &lt; 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. <h3>Conclusions</h3> Although community-dwelling individuals harboring a cysteine-altering <i>NOTCH3</i> 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 <i>NOTCH3</i> cysteine altering variants are associated with an extremely broad phenotypic spectrum, ranging from CADASIL to nonpenetrance.