You are here

Article Text

Article menu

Download PDFPDF

Heart failure and cardiomyopathies
Original research article
Lamin mutation location predicts cardiac phenotype severity: combined analysis of the published literature
  1. Gabriella Captur1,2,3,
  2. Eloisa Arbustini4,
  3. Petros Syrris3,
  4. Dina Radenkovic2,
  5. Ben O'Brien5,6,
  6. William J Mckenna3 and
  7. James C Moon2,3
  1. 1 UCL MRC Unit for Lifelong Health and Ageing, London, UK
  2. 2 Barts Heart Centre, The Cardiovascular Magnetic Resonance Imaging Unit, St Bartholomew’s Hospital, London, UK
  3. 3 Institute of Cardiovascular Science, University College London, London, UK
  4. 4 Center for Inherited Cardiovascular Diseases, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
  5. 5 Department of Perioperative Medicine, St Bartholomew's Hospital & Barts Heart Centre, London, UK
  6. 6 William Harvey Research Institute, Charterhouse Square, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  1. Correspondence to James C Moon; james{at}moonmail.co.uk

Abstract

Objective Two LMNA genotype–phenotype cardiac correlations are reported: first, that cardiac involvement in multisystem laminopathies prevails with mutations upstream of the nuclear localisation signal (NLS); second, that worse outcomes occur with non-missense (compared with missense) mutations. We tested whether LMNA mutation DNA location and mutation subtype can predict phenotype severity in patients with lamin heart disease.

Methods We used a semantic workflow platform and manual electronic literature search to identify published LMNA mutations with cardiac-predominant phenotype. Hierarchical cluster analysis (HCA) assembled lamin heart disease into classes based on phenotype severity. 176 reported causative mutations were classified and any relationships to mutation location/subtype assessed by contingency analysis.

Results More adverse phenotype was associated with mutation location upstream of the NLS (p=0.014, OR 2.38, 95% CI 1.19 to 4.80) but not with non-missense mutations (p=0.337, OR 1.36, 95% CI 0.72 to 2.57), although an association with non-missense mutations was identified in a subcluster with malignant ventricular arrhythmia (p=0.005, OR 2.64, 95% CI 0.76 to 9.21). HCA limited to the 65 mutations described on ClinVar as pathogenic/likely pathogenic showed similar findings (upstream of NLS, p=0.030, OR 4.78, 95% CI 1.28 to 17.83; non-missense, p=0.121, OR 2.64, 95% CI 0.76 to 9.21) as did analysis limited to pathogenic/likely pathogenic variants according to the American College of Medical Genetics and Genomics standards.

Conclusion Cardiac patients with an LMNA mutation located upstream versus downstream of the NLS have a more adverse cardiac phenotype, and some missense mutations can be as harmful as non-missense ones.

  • heart failure
  • systolic dysfunction
  • gene association

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/openhrt-2018-000915

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    View Full Text

    Footnotes

    • Contributors GC, PS and DR conducted the literature search. GC conducted the statistical analysis, wrote the manuscript and made the figures and tables. PS reviewed the genetic data. EA, WJM, BOB and JCM provided expert review of the manuscript.

    • Funding GC is supported by the National Institute for Health Research Rare Diseases Translational Research Collaboration to study the deep phenotype of lamin heart disease (NIHR RD-TRC, #171603). JCM is indirectly supported by the Biomedical Research Unit at Barts Hospital. PS is funded by the University College London Hospitals NIHR Biomedical Research Center and his research is supported by the Fondation Leducq.

    • Competing interests None declared.

    • Patient consent Not required.

    • Ethics approval Research ethics committee approval was not required for this analysis.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement All data for the study have been provided in the main manuscript or the online supplementary materials.