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How common are single gene mutations as a cause for lacunar stroke? A targeted gene panel study.

Accepted version
Peer-reviewed

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Article

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Authors

Tan, Rhea YY 
Traylor, Matthew 
Duarte, Daniel 

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.

Description

Keywords

Age of Onset, Aged, CADASIL, Cerebral Amyloid Angiopathy, Familial, Cerebral Small Vessel Diseases, Connective Tissue Diseases, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Migraine with Aura, Mutation, Stroke, Lacunar

Journal Title

Neurology

Conference Name

Journal ISSN

0028-3878
1526-632X

Volume Title

93

Publisher

Ovid Technologies (Wolters Kluwer Health)

Rights

All rights reserved
Sponsorship
British Heart Foundation (RG/16/4/32218)
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC 2012-2017)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Funding for the project was provided by the National Institute for Health Research (NIHR, grant number RG65966). This work was supported by a BHF Programme Grant (RG/16/4/32218). Infrastructural support was provided by the Cambridge University Hospitals Trust Biomedical Research Centre. RYYT is supported by the Agency for Science, Technology and Research (Singapore). KD is a HSST trainee supported by NHS Health Education England. HM is supported by a NIHR Senior Investigator award.