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Novel disease loci
Original research
Identification of known and unknown genes associated with mitral valve prolapse using an exome slice methodology
  1. Aniek L van Wijngaarden1,
  2. Yasmine L Hiemstra1,
  3. Tamara T Koopmann2,
  4. Claudia A L Ruivenkamp2,
  5. Emmelien Aten2,
  6. Martin J Schalij1,
  7. Jeroen J Bax1,
  8. Victoria Delgado1,
  9. Daniela Q C M Barge-Schaapveld2,
  10. Nina Ajmone Marsan1
  1. 1 Cardiology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands
  2. 2 Clinical Genetics, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands
  1. Correspondence to Dr Nina Ajmone Marsan, Cardiology, Leiden University Medical Center, Leiden, Zuid-Holland, Netherlands; N.Ajmone{at}lumc.nl

Abstract

Purpose Although a familial distribution has been documented, the genetic aetiology of mitral valve prolapse (MVP) is largely unknown, with only four genes identified so far: FLNA, DCHS1, DZIP1 and PLD1. The aim of this study was to evaluate the genetic yield in known causative genes and to identify possible novel genes associated with MVP using a heart gene panel based on exome sequencing.

Methods Patients with MVP were referred for genetic counselling when a positive family history for MVP was reported and/or Barlow’s disease was diagnosed. In total, 101 probands were included to identify potentially pathogenic variants in a set of 522 genes associated with cardiac development and/or diseases.

Results 97 (96%) probands were classified as Barlow’s disease and 4 (4%) as fibroelastic deficiency. Only one patient (1%) had a likely pathogenic variant in the known causative genes (DCHS1). However, an interesting finding was that 10 probands (11%) had a variant that was classified as likely pathogenic in six different, mostly cardiomyopathy genes: DSP (1×), HCN4 (1×), MYH6 (1×), TMEM67 (1×), TRPS1 (1×) and TTN (5×).

Conclusion Exome slice sequencing analysis performed in MVP probands reveals a low genetic yield in known causative genes but may expand the cardiac phenotype of other genes. This study suggests for the first time that also genes related to cardiomyopathy may be associated with MVP. This highlights the importance to screen these patients and their family for the presence of arrhythmias and of ‘disproportionate’ LV remodelling as compared with the severity of mitral regurgitation, unravelling a possible coexistent cardiomyopathy.

  • clinical genetics
  • valvar diseases

https://doi.org/10.1136/jmedgenet-2019-106715

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    Footnotes

    • Contributors ALvW: data collection, performing DNA analysis and writing the manuscript. YLH: supporting role in data collection and revision of the final version of the manuscript. TTK: DNA analysis, supporting role in writing the manuscript and revision of the final version of the manuscript. CALR: DNA analysis, supporting role in writing the manuscript and revision of the final version of the manuscript. EA: supporting role in data collection, writing the manuscript and revision of the final version of the manuscript. MJS: supporting role in planning of the study, writing the manuscript and revision of the final version of the manuscript. JJB: supporting role in planning of the study, writing the manuscript and revision of the final version of the manuscript. VD: supporting role in planning of the study, writing the manuscript and revision of the final version of the manuscript. DQCMB-S: wrote the study protocol and planned the study, supporting role in writing the manuscript and revision of the final version of the manuscript. NAM: wrote the study protocol and planned the study, supporting role in writing the manuscript and revision of the final version of the manuscript, supervisor.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests The Department of Cardiology of Leiden University Medical Center received unrestricted research grants from Abbott Vascular, Bayer, Bioventrix, Biotronik, Boston Scientific, Edwards Lifesciences, GE Healthcare and Medtronic. VD received speaker fees from Abbott Vascular, Edwards Lifesciences, GE Healthcare and Medtronic. NAM and JJB received speaker fees from Abbott Vascular. The remaining authors have nothing to disclose.

    • Patient consent for publication Not required.

    • Ethics approval The study complies with the Declaration of Helsinki and was approved by the institutional review board and medical ethical committee.

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

    • Data availability statement Data are available upon reasonable request.