Abstract
This study aimed to determine the prevalence and clinical features of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) caused by pathogenic mutations in the Phospholamban (PLN) gene. The study included 170 patients who had a confirmed diagnosis of ARVC and underwent PLN genetic screening using next-generation sequencing. The findings of this study provide valuable insights into the association between PLN mutations and ARVC, which can aid in the development of more effective diagnostic and treatment strategies for ARVC patients. Out of the patients evaluated, six had a rare pathogenic mutation in PLN with the same p.R14del variant. Family screening revealed that heterozygous carriers of p.R14del exhibited a definite ARVC phenotype. In clinical studies, individuals with the p.R14del mutation experienced a similar rate of malignant arrhythmia events as those with classic desmosome mutations. After adjusting for covariates, individuals with PLN mutations had a two point one seven times greater likelihood of experiencing transplant-related risks compared to those who did not possess PLN mutations (95% CI 1.08–6.82, p = 0.035). The accumulation of left ventricular fat and fibers is a pathological marker for ARVC patients with p.R14del mutations. In a cohort of 170 Chinese ARVC patients, three point five percent of probands had the PLN pathogenic variant (p.R14del) and all were female. Our data shows that PLN-related ARVC patients are at high risk for ventricular arrhythmias and heart failure, which requires clinical differentiation from classic ARVC. Furthermore, carrying the p.R14del mutation can be an independent prognostic risk factor in ARVC patients.
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Data Availability
Data relating to this article are available in the article itself or in its Supplementary material online.
Abbreviations
- ARVC:
-
Arrhythmogenic right ventricular cardiomyopathy
- PLN :
-
Phospholamban
- DCM:
-
Dilated cardiomyopathy
- HCM:
-
Hypertrophic cardiomyopathy
- SERCA2a:
-
Sarcoplasmic/endoplasmic reticulum Ca2+-dependent ATPase 2a
- ICD:
-
Implantable cardioverter defibrillator
- RFCA:
-
Radiofrequency current catheter ablation
- NYHA:
-
The New York Heart Association
- HT:
-
Heart transplantation
- NV-HT:
-
None variants-heart transplantation
- LV:
-
Left ventricular
- RV:
-
Right ventricular
- LVEDD:
-
Left ventricle end diastolic dimension
- RVEDD:
-
Right ventricle end diastolic dimension
- LVEF:
-
Left ventricle ejection fraction
- MACE:
-
Major arrhythmic cardiovascular events
- SCD:
-
Sudden cardiac death
- P:
-
Pathogenic
- LP:
-
Likely pathogenic
- VUS:
-
Uncertain significance
- LB:
-
Likely benign
- B:
-
Benign
- ACMG:
-
American College of Medical Genetics and Genomics
- ALV:
-
Anterior free wall of the left ventricle
- LLV:
-
Lateral free wall of left ventricular
- PLV:
-
Posterior free wall of the left ventricular
- ARV:
-
Anterior free wall of right ventricular
- PRV:
-
Posterior free wall of the right ventricular
- IVS:
-
The interventricular septum
- HGVS:
-
Human genome variation society
- COX:
-
Proportional hazards
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Acknowledgements
We gratefully appreciate the numerous sample donors for making this work possible.
Funding
This work was Supported by the National Natural Science Foundation for Distinguished Young Scholars of China (Grant No. 82125004), the Shenzhen Science and Technology Innovation Commission (Grant No. JCYJ20220818103414030), the National Natural Science Foundation of China (Grant No. 82300397), the key project of Shenzhen Basic Research Program (Natural Science Foundation of Shenzhen, Grant No. 20220241), and the Program for Guangdong Introducing Innovative and Enterpreneurial Teams (Grant No. 2019ZT08Y481).
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Conceived and designed the study: JS, XH and HM; Performed the experiments: MB, XC and ZS; Analyzed the data: HM, XH and MX; Prepared the manuscript: JS, XH and HM.
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All clinical investigations were conducted in accordance with the principles expressed in the Declaration of Helsinki. The study protocol was approved by the Ethics Committee Review Board of Fuwai Hospital.
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Mo, H., Hua, X., Bao, M. et al. A Heterozygous Phospholamban Variant (p.R14del) Leads to Left Ventricular Involvement and Heart Failure Phenotypes in Arrhythmogenic Right Ventricular Cardiomyopathy. Phenomics 4, 13–23 (2024). https://doi.org/10.1007/s43657-023-00126-w
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DOI: https://doi.org/10.1007/s43657-023-00126-w