How common are single gene mutations as a cause for lacunar stroke? A targeted gene panel study.
Tan, Rhea YY
Mapeta, Rutendo P
NIHR BioResource: Rare Diseases Consortium,
Lippincott Williams & Wilkins Ltd.
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Tan, R. Y., Traylor, M., Megy, K., Duarte, D., Deevi, S. V., Shamardina, O., Mapeta, R. P., et al. (2019). How common are single gene mutations as a cause for lacunar stroke? A targeted gene panel study.. Neurology, 93 (22), e2007-e2020. https://doi.org/10.1212/wnl.0000000000008544
Objectives To determine the frequency of rare and pertinent disease-causing variants in SVD-associated genes (such as NOTCH3, HTRA1, COL4A1, COL4A2, FOXC1, TREX1 and GLA) in cerebral small vessel disease (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 centres across the UK. Variants were filtered according to their frequency in control databases, predicted impact, presence in curated variant lists, and combined annotation dependent depletion (CADD) 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, two HTRA1 variants in two patients and one missense COL4A1 variant in one patient). Additionally, we identified twenty-nine variants of uncertain significance in 32 patients. Conclusion Rare monogenic variants account for about 1.5% of younger onset lacunar stroke. Most are CADASIL 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.
NIHR BioResource: Rare Diseases Consortium, Humans, Cerebral Amyloid Angiopathy, Familial, CADASIL, Connective Tissue Diseases, Age of Onset, Mutation, Aged, Middle Aged, Female, Male, Migraine with Aura, High-Throughput Nucleotide Sequencing, Cerebral Small Vessel Diseases, Stroke, Lacunar
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.
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)
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External DOI: https://doi.org/10.1212/wnl.0000000000008544
This record's URL: https://www.repository.cam.ac.uk/handle/1810/293257
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