Clinical Outcomes of CADASIL-Associated NOTCH3 Mutations in 451,424 European Ancestry Community Volunteers
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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a relatively rare hereditary small vessel disease resulting in neurological deficits . Stroke and transient ischaemic attack (TIA) are reported in the majority with symptomatic CADASIL, driving presentation in 71% in a large case series, migraine is common (23%) and life expectancy is reduced [1, 2]. CADASIL can also contribute to vascular dementia. The exact prevalence of CADASIL is unknown as it is under-recognised even in specialist stroke settings, but the minimum prevalence is estimated at 2–5 in 100,000 .
Previous CADASIL studies have generally involved genotyping for patients presenting with repeated strokes, with several missense (amino-acid substituting) mutations in the NOTCH3 gene reported . Many, often rare, mutations have been linked to CADASIL. However, population-based estimates of the predictive value of NOTCH3 missense mutations in community samples are unknown. With increasing availability of genotyping, including in clinical biobanks and direct to consumers, data are needed on the true penetrance of NOTCH3 mutations.
There were 8596 heterozygotes for rs35769976 and only 44 G allele homozygotes (0.01% of 451,424), so we grouped homozygotes and heterozygotes. The mean age of the sample was 56.8 years (SD 8.0, median 58, IQR 12). Participants with at least one rs35769976 G allele had a slightly increased diastolic BP (coefficient 0.24, 0.0079 to 0.47; p value = 0.043). There were no strokes or TIAs in the G allele homozygotes and 77 in heterozygotes. The rs35769976 variant was not associated with incident stroke or TIA, CHD or all-cause mortality.
In a European Ancestry community volunteer biobank, we have shown that only two potentially pathogenic NOTCH3 missense variants were ascertained in array genotyping data with imputation. rs201680145, previously reported as pathogenic by two sources , was associated with elevated systolic and diastolic BP, plus substantially increased risk of incident stroke or TIA. However, the great majority of rs35769976 carriers did not have a stroke or TIA, suggesting that this mutation is associated with a milder clinical course. If these mutations were associated with high rates of serious strokes, we would expect prevalence of the mutations to be lower at older ages, but neither mutation was associated with age in UK biobank. A limitation of our analysis is that the maximum age at end follow-up was 80 years. However, as the cohort included those between 41 and 70 years at baseline, with up to 10-year follow-up, the important time for early strokes is captured. In addition, while 10-year follow-up is longer than in most reported CADASIL studies, data on even longer follow-ups would be helpful. This would also allow analysis of repeat events in individuals, as numbers with recurrent stroke or TIA in this cohort were too small to analyse.
This study suggests that potentially pathogenic NOTCH3 missense mutations seen in large European ancestry array genotyped biobanks have relatively limited CADASIL risk profiles. Caution is needed in responding to incidental data on these mutations in community volunteer samples. More work is needed to establish whether co-factors (including higher blood pressures) modify risks of clinical outcomes.
This report is independent research supported by the National Institute for Health Research (NIHR Doctoral Research Fellowship, Dr. Jane Masoli, DRF-2014-07-177).
Compliance with Ethical Standards
This research has been conducted using the UK Biobank resource under Application Number 14631. We thank UK Biobank participants and coordinators for this dataset. Informed consent was obtained from all individual participants included in the study.
Conflict of Interest
The authors declare that they have no conflict of interest.
The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.
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