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Shared Desmosome Gene Findings in Early and Late Onset Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

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Abstract

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited form of cardiomyopathy with low penetrance and variable expressivity. Dominant mutations and rare polymorphisms in desmosome genes are frequently identified. We reasoned that individuals with earlier onset disease would have more frequent desmosome gene mutations and rare polymorphisms. Three groups were compared: Young with symptoms attributable to ARVD/C or a diagnosis of ARVD/C at age of 21 years or earlier, Middle with first symptoms or diagnosis age of 22–49 years, and Late with first symptoms or diagnosis at age of 50 or more years. deoxyribonucleic acid (DNA) sequence analysis was performed on five cardiac desmosome genes, and the presence of mutations and rare missense polymorphisms was compared among the three groups. In the entire Young cohort, 20 (67%) had one or more cardiac desmosome gene mutations. The prevalence of cardiac desmosome gene mutations was similar in the Middle (48%) and Late (53%) cohorts (P = 0.23). Similar numbers of individuals in each cohort had more than one desmosome gene mutation, although the numbers are too small for statistical comparisons. The prevalence of certain rare missense DNA variants was not different among the cohorts (P = 0.71), yet these rare missense alleles were more prevalent in the overall study cohort of 112 ARVD/C participants compared to 100 race-matched controls (P = 0.027). The presence of these variants did not associate with the age of onset of ARVD/C or ventricular tachycardia. These findings highlight the complex interplay of environmental and genetic factors contributing to this condition.

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Acknowledgments

This work was supported by funding from the National Institutes of Health (HL088072 to DPJ), the France-Merrick Foundation, JHU Friends in Red, and the Jeff Cooper CARE Foundation. The authors would also like to acknowledge the Johns Hopkins ARVD Program (http://www.arvd.com), which is supported by the Bogle Foundation, the Campanella family, the Wilmerding Endowment, the Dr. Francis P Chiaramonte Foundation, the Healing Hearts Foundation, Boston Scientific, Medtronic, and St Jude Medical. BY Tan was supported by funds from the National Medical Research Council Medical Research Fellowship and the Health Manpower Development Plan Fellowship by the Ministry of Health, Singapore.

Conflicts of Interest

Dr. Hugh Calkins receives honoraria for lectures from Boston Scientific, Medtronic, and St. Jude Medical and is a consultant for Medtronic. The authors have no other potential conflicts of interest to disclose.

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Authors and Affiliations

  1. Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Boon Yew Tan, Rahul Jain, A. Dénise den Haan, Yan Chen, Darshan Dalal, Harikrishna Tandri, Nuria Amat-Alarcon, Amy Daly, Crystal Tichnell, Cynthia James, Hugh Calkins & Daniel P. Judge

  2. Department of Cardiology, National Heart Centre, Singapore, Singapore

    Boon Yew Tan

  3. Division of Cardiology, Johns Hopkins University, Ross Building, #1049; Rutland Avenue, Baltimore, MD, 21205, USA

    Daniel P. Judge

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  1. Boon Yew Tan
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Correspondence to Daniel P. Judge.

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Table S1

Clinical and genetic characteristics of participants. (DOC 42.3 kb)

Fig. S1

Conservation at sites of novel mutations in the Young cohort. Conservation of the mutated amino acid in five novel missense mutations. Amino acids are represented by their standard abbreviations (E Glutamate, K Lysine, G Glycine, T Threonine). ↓ indicates site of mutation. Species are shown by their standard nomenclature. (DOC 41.0 kb)

Fig. S2

Conservation at sites of novel mutations in the Late cohort. Conservation of the mutated amino acid in three novel missense mutations. Amino acids are represented by their standard abbreviations (D aspartate, E glutamate, V valine). ↓ indicates site of mutation. Species are shown by their standard nomenclature. (DOC 31.5 kb)

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Tan, B.Y., Jain, R., den Haan, A.D. et al. Shared Desmosome Gene Findings in Early and Late Onset Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. J. of Cardiovasc. Trans. Res. 3, 663–673 (2010). https://doi.org/10.1007/s12265-010-9224-4

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