Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank

Abstract

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.

NOTCH3 variants are more common than expected in the general population and associated with stroke and vascular dementia: an analysis of 200 000 participants

“…Studies have mostly been conducted on anonymised genome-sequencing databases, 7 and it is unclear whether such apparently 'asymptomatic' variants have clinical implications. 9 It has been demonstrated that such variants are more likely to be in EGFR domains 7-34, while variants within clinical CADASIL cases are more likely, although not exclusively, in domains 1-6. 10 To determine whether these variants increase disease, analysis of sequencing databases in which clinical data are also available is required.…”

NOTCH3 variants are common in the general population and associated with stroke and vascular dementia: an analysis of 200,000 participants

“…CADASIL is reported to be rare, with an estimated disease prevalence of 4 per 100,000 individuals in UK populations. [5,6] In contrast, recent studies have demonstrated an increased frequency of cysteine-changing NOTCH3 variants in population databases,[7,9] but these have been anonymised databases making it impossible to determine whether these variants associate with clinical disease. A very recent report from the United States Geisinger database suggested such variants associated with an increased risk of stroke and MRI features of SVD, although no association was found with dementia.…”

“…Studies have mostly been conducted on anonymised genome-sequencing databases, [7] and it is unclear whether such apparently 'asymptomatic' variants have clinical implications. [9] It has been demonstrated that such variants are more likely to be in EGFR domains 7-34, while variants within clinical CADASIL cases are more likely, although not exclusively, in domains 1-6. [10] To determine whether these variants increase disease, analysis of sequencing databases in which clinical data is also available is required.…”

Contribution of “Omic” Studies to the Understanding of Cadasil. A Systematic Review

“…In fact, because of the creation of biobanks, which are projects that aggregate and harmonize exome and genome sequencing data from a wide variety of large-scale sequencing studies, it has been possible to further profile mutations affecting cysteine residues in Notch3 in a significant number of individuals. In the Genome Aggregation Database (gnomAD, , accessed on 27 May 2021), the UK Biobank (UKB, , accessed on 27 May 2021) and the Geisinger DiscovEHR ( , accessed on 27 May 2021), a prevalence of 1.4–3.4/1000 subjects carrying NOTCH3 variants that were considered pathogenic were established [ 17 , 18 , 19 , 20 , 21 ] ( Figure 2 ), and 9/1000 in the Taiwan Biobank ( , accessed on 27 May 2021) [ 22 ], the latter high frequency is in line with the UKB observation of enrichment of pathogenic mutations in NOTCH3 in Asians [ 19 ].…”