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Novel disease loci
Short report
FLNC truncations cause arrhythmogenic right ventricular cardiomyopathy
  1. Francesca Brun1,
  2. Marta Gigli1,
  3. Sharon L Graw2,
  4. Daniel P Judge3,
  5. Marco Merlo1,
  6. Brittney Murray4,
  7. Hugh Calkins4,
  8. Gianfranco Sinagra1,
  9. Matthew RG Taylor2,5,
  10. Luisa Mestroni2,
  11. Cynthia A James4
  1. 1 Cardiovascular Department and Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Friuli-Venezia Giulia, Italy
  2. 2 Cardiovascular Institute, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
  3. 3 Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina, USA
  4. 4 Division of Cardiology, Johns Hopkins, Baltimore, Maryland, USA
  5. 5 Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
  1. Correspondence to Professor Luisa Mestroni, Cardiovascular Institute, University of Colorado Anschutz Medical Campus, Aurora 80045-2581, Colorado, USA; luisa.mestroni{at}CUAnschutz.edu

Abstract

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease that affects predominantly the right ventricle and is part of the spectrum of arrythmogenic cardiomyopathies (ACMs). ARVC is a genetic condition; however, a pathogenic gene variant is found in only half of patients.

Objective Filamin C gene truncations (FLNCtv) have recently been identified in dilated cardiomyopathy with ventricular arrhythmia and sudden cardiac death, a phenotype partially overlapping with ARVC and part of the ACM spectrum. We hypothesised that FLNCtv could be a novel gene associated with ARVC.

Methods One hundred fifty-six patients meeting 2010 ARVC Task Force Criteria and lacking variants in known ARVC genes were evaluated for FLNC variants. Available family members were tested for cosegregation.

Results We identified two unique FLNCtv variants in two families (c.6565 G>T, p.Glu2189Ter and c.8107delG, p.Asp2703ThrfsTer69), with phenotypes of dominant RV disease fulfilling ‘definite’ diagnosis of ARVC according to the 2010 Task Force Criteria. Variants in other cardiomyopathy genes were excluded in both kindreds, and segregation analysis revealed that p.Asp2703ThrfsTer69 was a de novo variant. In both families, the disease phenotype was characterised by prominent ventricular arrhythmias and sudden cardiac arrest.

Conclusion The identification of FLNCtv as a novel cause of ARVC in two unrelated families expands the spectrum of ARVC non-desmosome disease genes for this disorder. Our findings should prompt inclusion of FLNC genetic testing in ARVC to improve diagnostic yield and testing of at-risk relatives in ARVC.

  • arrhythmogenic cardiomyopathy
  • filamin C
  • sudden cardiac death
  • arrhythmias
  • dilated cardiomyopathy
  • arrhythmogenic right ventricular cardiomyopathy

https://doi.org/10.1136/jmedgenet-2019-106394

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    Footnotes

    • Contributors FB, MG, MM, BM: clinical characterisation of family members, data analysis and final approval of the manuscript submitted. SLG: design, analysis and interpretation of targeted sequencing data; revising critically the manuscript for important intellectual content; final approval of the manuscript submitted. MT, GS, DPJ, HC, LM, CJ: conception, design, analysis and interpretation of data; drafting of the manuscript and revising it critically for important intellectual content; final approval of the manuscript submitted.

    • Funding This study was supported by the NIH R01 HL69071, HL116906, NCATS/CTSA UL1 TR001082 and AHA17GRNT33670495 (LM); NIH 1K23HI067915 and R01HL109209 (MT); 2UM1HG006542 and NCATS UL1 TR001079 (HC). This work was also supported in part by the Trans-Atlantic Network of Excellence grants from the Foundation Leducq (14-CVD 03 and 16-CVD 02) and the EU FP7 SarcoSi IRSES. The Johns Hopkins ARVD/C Program is supported by the Leonie-Wild Foundation, the Francis P. Chiaramonte Private Foundation, the Leyla Erkan Family Fund for ARVD Research, the Dr. Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins, the Bogle Foundation, the Healing Hearts Foundation, the Campanella family, the Patrick J. Harrison Family, the Peter French Memorial Foundation and the Wilmerding Endowments.

    • Competing interests None declared.

    • Patient consent for publication Not required.

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