Skip to main content
Advertisement
  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Genetics
    • Neuroimmunology & Neuroinflammation
    • Education
  • Online Sections
    • Neurology Video Journal Club
    • Inclusion, Diversity, Equity, Anti-racism, & Social Justice (IDEAS)
    • Innovations in Care Delivery
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Null Hypothesis
    • Patient Pages
    • Topics A-Z
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center

Advanced Search

Main menu

  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Genetics
    • Neuroimmunology & Neuroinflammation
    • Education
  • Online Sections
    • Neurology Video Journal Club
    • Inclusion, Diversity, Equity, Anti-racism, & Social Justice (IDEAS)
    • Innovations in Care Delivery
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Null Hypothesis
    • Patient Pages
    • Topics A-Z
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center
  • Home
  • Latest Articles
  • Current Issue
  • Past Issues
  • Residents & Fellows

User menu

  • Subscribe
  • My Alerts
  • Log in

Search

  • Advanced search
Neurology
Home
The most widely read and highly cited peer-reviewed neurology journal
  • Subscribe
  • My Alerts
  • Log in
Site Logo
  • Home
  • Latest Articles
  • Current Issue
  • Past Issues
  • Residents & Fellows

Share

November 26, 2019; 93 (22) ArticleOpen Access

How common are single gene mutations as a cause for lacunar stroke?

A targeted gene panel study

Rhea Y.Y. Tan, Matthew Traylor, View ORCID ProfileKaryn Megy, Daniel Duarte, View ORCID ProfileSri V.V. Deevi, Olga Shamardina, Rutendo P. Mapeta, NIHR BioResource: Rare Diseases Consortium, Willem H. Ouwehand, Stefan Gräf, Kate Downes, Hugh S. Markus
First published November 12, 2019, DOI: https://doi.org/10.1212/WNL.0000000000008544
Rhea Y.Y. Tan
From the Stroke Research Group, Department of Clinical Neurosciences (R.Y.Y.T., M.T., H.S.M.), Department of Haematology (K.M., D.D., S.V.V.D., O.S., R.P.M., W.H.O., S.G., K.D.), and Division of Respiratory Medicine, Department of Medicine (S.G.), University of Cambridge; and NIHR BioResource: Rare Diseases (K.M., S.V.V.D., O.S., R.P.M., W.H.O., S.G., H.S.M.), Biomedical Campus, Cambridge, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthew Traylor
From the Stroke Research Group, Department of Clinical Neurosciences (R.Y.Y.T., M.T., H.S.M.), Department of Haematology (K.M., D.D., S.V.V.D., O.S., R.P.M., W.H.O., S.G., K.D.), and Division of Respiratory Medicine, Department of Medicine (S.G.), University of Cambridge; and NIHR BioResource: Rare Diseases (K.M., S.V.V.D., O.S., R.P.M., W.H.O., S.G., H.S.M.), Biomedical Campus, Cambridge, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Karyn Megy
From the Stroke Research Group, Department of Clinical Neurosciences (R.Y.Y.T., M.T., H.S.M.), Department of Haematology (K.M., D.D., S.V.V.D., O.S., R.P.M., W.H.O., S.G., K.D.), and Division of Respiratory Medicine, Department of Medicine (S.G.), University of Cambridge; and NIHR BioResource: Rare Diseases (K.M., S.V.V.D., O.S., R.P.M., W.H.O., S.G., H.S.M.), Biomedical Campus, Cambridge, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Karyn Megy
Daniel Duarte
From the Stroke Research Group, Department of Clinical Neurosciences (R.Y.Y.T., M.T., H.S.M.), Department of Haematology (K.M., D.D., S.V.V.D., O.S., R.P.M., W.H.O., S.G., K.D.), and Division of Respiratory Medicine, Department of Medicine (S.G.), University of Cambridge; and NIHR BioResource: Rare Diseases (K.M., S.V.V.D., O.S., R.P.M., W.H.O., S.G., H.S.M.), Biomedical Campus, Cambridge, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sri V.V. Deevi
From the Stroke Research Group, Department of Clinical Neurosciences (R.Y.Y.T., M.T., H.S.M.), Department of Haematology (K.M., D.D., S.V.V.D., O.S., R.P.M., W.H.O., S.G., K.D.), and Division of Respiratory Medicine, Department of Medicine (S.G.), University of Cambridge; and NIHR BioResource: Rare Diseases (K.M., S.V.V.D., O.S., R.P.M., W.H.O., S.G., H.S.M.), Biomedical Campus, Cambridge, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Sri V.V. Deevi
Olga Shamardina
From the Stroke Research Group, Department of Clinical Neurosciences (R.Y.Y.T., M.T., H.S.M.), Department of Haematology (K.M., D.D., S.V.V.D., O.S., R.P.M., W.H.O., S.G., K.D.), and Division of Respiratory Medicine, Department of Medicine (S.G.), University of Cambridge; and NIHR BioResource: Rare Diseases (K.M., S.V.V.D., O.S., R.P.M., W.H.O., S.G., H.S.M.), Biomedical Campus, Cambridge, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rutendo P. Mapeta
From the Stroke Research Group, Department of Clinical Neurosciences (R.Y.Y.T., M.T., H.S.M.), Department of Haematology (K.M., D.D., S.V.V.D., O.S., R.P.M., W.H.O., S.G., K.D.), and Division of Respiratory Medicine, Department of Medicine (S.G.), University of Cambridge; and NIHR BioResource: Rare Diseases (K.M., S.V.V.D., O.S., R.P.M., W.H.O., S.G., H.S.M.), Biomedical Campus, Cambridge, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
From the Stroke Research Group, Department of Clinical Neurosciences (R.Y.Y.T., M.T., H.S.M.), Department of Haematology (K.M., D.D., S.V.V.D., O.S., R.P.M., W.H.O., S.G., K.D.), and Division of Respiratory Medicine, Department of Medicine (S.G.), University of Cambridge; and NIHR BioResource: Rare Diseases (K.M., S.V.V.D., O.S., R.P.M., W.H.O., S.G., H.S.M.), Biomedical Campus, Cambridge, UK.
Willem H. Ouwehand
From the Stroke Research Group, Department of Clinical Neurosciences (R.Y.Y.T., M.T., H.S.M.), Department of Haematology (K.M., D.D., S.V.V.D., O.S., R.P.M., W.H.O., S.G., K.D.), and Division of Respiratory Medicine, Department of Medicine (S.G.), University of Cambridge; and NIHR BioResource: Rare Diseases (K.M., S.V.V.D., O.S., R.P.M., W.H.O., S.G., H.S.M.), Biomedical Campus, Cambridge, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stefan Gräf
From the Stroke Research Group, Department of Clinical Neurosciences (R.Y.Y.T., M.T., H.S.M.), Department of Haematology (K.M., D.D., S.V.V.D., O.S., R.P.M., W.H.O., S.G., K.D.), and Division of Respiratory Medicine, Department of Medicine (S.G.), University of Cambridge; and NIHR BioResource: Rare Diseases (K.M., S.V.V.D., O.S., R.P.M., W.H.O., S.G., H.S.M.), Biomedical Campus, Cambridge, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kate Downes
From the Stroke Research Group, Department of Clinical Neurosciences (R.Y.Y.T., M.T., H.S.M.), Department of Haematology (K.M., D.D., S.V.V.D., O.S., R.P.M., W.H.O., S.G., K.D.), and Division of Respiratory Medicine, Department of Medicine (S.G.), University of Cambridge; and NIHR BioResource: Rare Diseases (K.M., S.V.V.D., O.S., R.P.M., W.H.O., S.G., H.S.M.), Biomedical Campus, Cambridge, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hugh S. Markus
From the Stroke Research Group, Department of Clinical Neurosciences (R.Y.Y.T., M.T., H.S.M.), Department of Haematology (K.M., D.D., S.V.V.D., O.S., R.P.M., W.H.O., S.G., K.D.), and Division of Respiratory Medicine, Department of Medicine (S.G.), University of Cambridge; and NIHR BioResource: Rare Diseases (K.M., S.V.V.D., O.S., R.P.M., W.H.O., S.G., H.S.M.), Biomedical Campus, Cambridge, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Full PDF
Short Form
Citation
How common are single gene mutations as a cause for lacunar stroke?
A targeted gene panel study
Rhea Y.Y. Tan, Matthew Traylor, Karyn Megy, Daniel Duarte, Sri V.V. Deevi, Olga Shamardina, Rutendo P. Mapeta, NIHR BioResource: Rare Diseases Consortium, Willem H. Ouwehand, Stefan Gräf, Kate Downes, Hugh S. Markus
Neurology Nov 2019, 93 (22) e2007-e2020; DOI: 10.1212/WNL.0000000000008544

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Permissions

Make Comment

See Comments

Downloads
1691

Share

  • Article
  • Figures & Data
  • Info & Disclosures
Loading

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.

View Full Text

Disputes & Debates: Rapid online correspondence

No comments have been published for this article.
Comment

REQUIREMENTS

If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org

Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.

If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.

Submission specifications:

  • Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
  • Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
  • Submit only on articles published within 6 months of issue date.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Disputes & Debates

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Publishing Agreement Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
  • Article
    • Abstract
    • Glossary
    • Methods
    • Results
    • Discussion
    • Study funding
    • Disclosure
    • Acknowledgment
    • Appendix Authors
    • Footnotes
    • References
  • Figures & Data
  • Info & Disclosures
Advertisement

Related Articles

  • No related articles found.

Topics Discussed

  • All Genetics
  • All Cerebrovascular disease/Stroke
  • CADASIL
  • Stroke in young adults

Alert Me

  • Alert me when eletters are published
Neurology: 99 (6)

Articles

  • Ahead of Print
  • Current Issue
  • Past Issues
  • Popular Articles
  • Translations

About

  • About the Journals
  • Ethics Policies
  • Editors & Editorial Board
  • Contact Us
  • Advertise

Submit

  • Author Center
  • Submit a Manuscript
  • Information for Reviewers
  • AAN Guidelines
  • Permissions

Subscribers

  • Subscribe
  • Activate a Subscription
  • Sign up for eAlerts
  • RSS Feed
Site Logo
  • Visit neurology Template on Facebook
  • Follow neurology Template on Twitter
  • Visit Neurology on YouTube
  • Neurology
  • Neurology: Clinical Practice
  • Neurology: Genetics
  • Neurology: Neuroimmunology & Neuroinflammation
  • Neurology: Education
  • AAN.com
  • AANnews
  • Continuum
  • Brain & Life
  • Neurology Today

Wolters Kluwer Logo

Neurology | Print ISSN:0028-3878
Online ISSN:1526-632X

© 2022 American Academy of Neurology

  • Privacy Policy
  • Feedback
  • Advertise