Abstract
Objectives To determine the frequency of rare and pertinent disease-causing variants in small vessel disease (SVD)-associated genes (such as NOTCH3, HTRA1, COL4A1, COL4A2, FOXC1, TREX1, and GLA) in cerebral SVD, we performed targeted gene sequencing in 950 patients with younger-onset apparently sporadic SVD stroke using a targeted sequencing panel.
Methods We designed a high-throughput sequencing panel to identify variants in 15 genes (7 known SVD genes, 8 SVD-related disorder genes). The panel was used to screen a population of 950 patients with younger-onset (≤70 years) MRI-confirmed SVD stroke, recruited from stroke centers across the United Kingdom. Variants were filtered according to their frequency in control databases, predicted effect, presence in curated variant lists, and combined annotation dependent depletion scores. Whole genome sequencing and genotyping were performed on a subset of patients to provide a direct comparison of techniques. The frequency of known disease-causing and pertinent variants of uncertain significance was calculated.
Results We identified previously reported variants in 14 patients (8 cysteine-changing NOTCH3 variants in 11 patients, 2 HTRA1 variants in 2 patients, and 1 missense COL4A1 variant in 1 patient). In addition, we identified 29 variants of uncertain significance in 32 patients.
Conclusion Rare monogenic variants account for about 1.5% of younger onset lacunar stroke. Most are cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy variants, but the second most common gene affected is HTRA1. A high-throughput sequencing technology platform is an efficient, reliable method to screen for such mutations.
Glossary
- CADASIL=
- cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy;
- CARASIL=
- cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy;
- CI=
- confidence interval;
- CNV=
- copy number variant;
- DHPLC=
- denaturing high-performance liquid chromatography;
- FLAIR=
- fluid-attenuated inversion recovery;
- gnomAD=
- genome aggregation database;
- HTS=
- high-throughput sequencing;
- ICH=
- intracerebral hemorrhage;
- NIHR=
- National Institute for Health Research;
- SVD=
- small vessel disease;
- WES=
- whole-exome sequencing;
- WGS=
- whole-genome sequencing;
- WMH=
- white matter hyperintensities
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Coinvestigators are listed at links.lww.com/WNL/A1000.
The Article Processing Charge was funded by University of Cambridge.
- Received January 10, 2019.
- Accepted in final form June 10, 2019.
- Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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