Identification of established arrhythmogenic right ventricular cardiomyopathy mutation in a patient with the contrasting phenotype of hypertrophic cardiomyopathy
© The Author(s). 2017
Received: 29 September 2016
Accepted: 27 February 2017
Published: 3 March 2017
Advances in the nucleic acid sequencing technologies have ushered in the era of genetic-based “precision medicine”. Applications of the genetic discoveries to practice of medicine, however, are hindered by phenotypic variability of the genetic variants. The report illustrates extreme pleiotropic phenotypes associated with an established causal mutation for hereditary cardiomyopathy.
We report a 61-year old white female who presented with syncope and echocardiographic and cardiac magnetic resonance (CMR) imaging findings consistent with the diagnosis of hypertrophic cardiomyopathy (HCM). The electrocardiogram, however, showed a QRS pattern resembling an Epsilon wave, a feature of arrhythmogenic right ventricular cardiomyopathy (ARVC). Whole exome sequencing (mean depth of coverage of exons 178X) analysis did not identify a pathogenic variant in the known HCM genes but identified an established causal mutation for ARVC. The mutation involves a canonical splice accepter site (c.2146-1G > C) in the PKP2 gene, which encodes plakophillin 2. Sanger sequencing confirmed the mutation. PKP2 is the most common causal gene for ARVC but has not been implicated in HCM. Findings on echocardiography and CMR during the course of 4-year follow up showed septal hypertrophy and a hyperdynamic left ventricle, consistent with the diagnosis of HCM. However, neither baseline nor follow up echocardiography and CMR studies showed evidence of ARVC. The right ventricle was normal in size, thickness, and function and there was no evidence of fibro-fatty infiltration in the myocardium.
The patient carries an established pathogenic mutation for ARVC and a subtle finding of ARVC but exhibits the classic phenotype of HCM, a contrasting phenotype to ARVC. The case illustrates the need for detailed phenotypic characterization for patients with hereditary cardiomyopathies as well as the challenges physicians face in applying the genetic discoveries in practicing genetic-based “precision medicine”.
KeywordsCardiomyopathy Mutation Plakophilin 2 Precision medicine Genetics Case report
Technological advances in nucleic acid sequencing have enabled identification of the genetic variants (GVs) across the genome and have ushered in utilization of the GVs in practice of medicine. Genetic-based “personalized medicine” or “precision medicine” advocates for exploiting the information content of the GVs to determine susceptibility to disease, individualize therapy, in order to maximize gain and to reduce the side effects, prognosticate, and assess the clinical outcomes. In a broader definition, “precision medicine” promotes utilizing various individualized indicators, encompassing metabolomics, transcriptomics, genomics, proteomics, environmental exposures, and microbiome, among others, to tailor the medical management of an individual.
Single gene disorders, whereby the effect size of the GVs are relatively large, are the prototypic diseases for the applications of genetic-based “precision medicine”. However, there is considerable phenotypic variability and pleiotropic effects, even in single gene disorders. The variability typically results from different mutations in a given causal gene causing distinct phenotypes. The point has been illustrated for hereditary cardiomyopathies, whereby different mutations in genes encoding sarcomere proteins can cause either hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM) and affect severity of the phenotypic expression [1–3]. However, phenotypic variability of a specific mutation associated with two distinct cardiomyopathy phenotypes is less well appreciated. We report an interesting patient who exhibits the classic phenotype of hypertrophic cardiomyopathy (HCM) but carries a rare mutation that has been established to cause the contrasting phenotype of arrhythmogenic right ventricular cardiomyopathy (ARVC).
Stop gain, splicing (2 bp of canonical site), and any insertion or deletion
Pathogenic or likely pathogenic as annotated by ClinVar 
Coverage of known HCM and HCM-phenocopy genes in the WES data
Proportion of coding region covered at given level
Variants identified in the WES data whose corresponding genes have been associated with mendelian disorders
Gene containing a pathogenic variant
Disease/Phenotype listed in OMIM
Phenotype in the proband
• Bethlem myopathy 1
• Ullrich congenital muscular dystrophy 1
• Bethlem myopathy 1
• Dystonia 27
• Ullrich congenital muscular dystrophy 1
• Fanconi anemia
• Night blindness, Congenital stationary (complete)
• 1E, autosomal recessive
• ?Spondylocostal dysostosis 3\autosomal recessive
• Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1
• Lateral meningocele syndrome
• ?Myofibromatosis, infantile 2
• Arrhythmogenic right ventricular cardiomyopathy
• Premature ovarian failure 2B
• Holoprosencephaly 4
Although different mutations in a single gene can cause distinct phenotypes, the observed association of a single mutation with two distinct and contrasting phenotypes, namely HCM and ARVC, is rare, if not unique. The former is characterized by cardiac myocyte hypertrophy, classically in the left ventricle and the latter by myocyte atrophy, apoptosis, and excess fibro-adipocytes, classically in the right ventricle. The patient had a clear clinical diagnosis of HCM, as evidenced by the presence of asymmetric cardiac hypertrophy with a predominant involvement of the interventricular septum, on multiple echocardiograms and CMR, in the absence of a secondary cause, such as systemic arterial hypertension or aortic stenosis. However, the patient did not meet the clinical criteria for the diagnosis of ARVC, despite carrying a well-established mutation in the most common causal gene for ARVC . The QRS pattern resembling an epsilon wave is considered a major, albeit insufficient, diagnostic criterion for the ARVC, evoking possible ARVC . The absence of a full ARVC phenotype in the proband might reflect incomplete penetrance, which is a known feature of the PKP2 variants . The Epsilon wave observed in the proband is not a feature of HCM but is a major diagnostic criterion for ARVC. The electrocardiographic pattern also resembles the pattern observed in Brugada syndrome , which is also associated with the PKP2 mutations . However, cardiac hypertrophy is not a feature of the Brugada syndrome.
The published evidence for the pathogenic role of the c.2146-1G > C variant in ARVC is strong [11–13]. However, its causal role in HCM is uncertain. Rare variants, including the pathogenic variants, are population-specific. Consequently, detection of a pathogenic variant, previously identified as a disease-causing variant, in a single individual is insufficient to imply causality. Indeed, unambiguous ascertainment of genetic causality, regardless of the causal gene and variant, is exceedingly challenging if not impossible. HCM in this patient might be caused by undetected pathogenic variants, structural variants, and variants did not meet the filtering criteria . The exome of this patient also contained a rare variant in the OBSCN gene, which is a candidate gene for DCM but not an established causal gene for HCM . As shown in Table 1, WES had provided an excellent coverage to 15 known HCM and HCM-phenocopy genes. Thus, it is very unlikely that a pathogenic variant in the common HCM gene was undetected. Finally, it is also possible that a copy number variant or a large deletion, not detected by whole exome sequencing, is responsible for HCM in this case, albeit such variants are found in < 1% of HCM cases . Thus, one cannot exclude concomitant presence of HCM and ARVC phenotypes in this case.
The case illustrated extreme phenotypic pleiotropy associated with a PKP2 mutation, which is an established causal mutation for ARVC and yet this pathogenic variant was found in a patient with the well-defined contrasting phenotype of HCM. The diversity of the phenotypic expression of GVs does not diminish the clinical utilities of genetic testing in hereditary cardiomyopathies. To the contrary, the findings emphasize the need for better understanding of the phenotypic variability associated with the GVs by placing the focus on detailed phenotypic and genetic characterization of the patient. The ambiguities in genotype-phenotype correlation in this case illustrate the challenges physicians face in applying the genetic discoveries to the practice medicine. To quote Sir William Osler, the practice of “medicine is a science of uncertainty and an art of probability”. It seems to remains so, even in the era of “precision medicine”.
Cardiac magnetic resonance imaging
Whole exome sequencing
This work was supported in part by grants from NIH, National Heart, Lung and Blood Institute (NHLBI, R01 HL088498, 1R01HL132401, and R34 HL105563), Leducq Foundation (14 CVD 03), Roderick MacDonald Foundation (13RDM005), TexGen Fund from Greater Houston Community Foundation, Texas Heart Institute Foundation, and George and Mary Josephine Hamman Foundation.
Availability of data and materials
All data, without identifiers, will be made available per request. The contact person is A.J. Marian, M.D., email: Ali.J.Marian@uth.tmc.edu.
MB and LL analyzed whole exome data, YT collected the clinical data, BC performed and analyzed cardiac magnetic resonance imaging, and AJM supervised all components of the study, analyzed the phenotype data, and wrote the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Consent was obtained from the proband and her half-sister about publication of clinical and genetic information. The proband also provided consent for publication of data on her family history (members are deceased individuals).
Ethics approval and consent to participate
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell. 1990;62(5):999–1006.View ArticlePubMedGoogle Scholar
- Marian AJ, Mares Jr A, Kelly DP, Yu QT, Abchee AB, Hill R, Roberts R. Sudden cardiac death in hypertrophic cardiomyopathy. Variability in phenotypic expression of beta-myosin heavy chain mutations. Eur Heart J. 1995;16(3):368–76.View ArticlePubMedGoogle Scholar
- Kamisago M, Sharma SD, DePalma SR, Solomon S, Sharma P, McDonough B, Smoot L, Mullen MP, Woolf PK, Wigle ED, et al. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med. 2000;343(23):1688–96.View ArticlePubMedGoogle Scholar
- Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010;26(5):589–95.View ArticlePubMedPubMed CentralGoogle Scholar
- Rimmer A, Phan H, Mathieson I, Iqbal Z, Twigg SR, Consortium WGS, Wilkie AO, McVean G, Lunter G. Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications. Nat Genet. 2014;46(8):912–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Bainbridge MN, Armstrong GN, Gramatges MM, Bertuch AA, Jhangiani SN, Doddapaneni H, Lewis L, Tombrello J, Tsavachidis S, Liu Y, et al. Germline mutations in shelterin complex genes are associated with familial glioma. J Natl Cancer Inst. 2015;107(1):384.View ArticlePubMedGoogle Scholar
- http://www.ncbi.nlm.nih.gov/clinvar/. Accessed 3 Dec 2016.
- http://mutationassessor.org/r3/. Accessed 3 Dec 2016.
- http://genetics.bwh.harvard.edu/pph2/. Accessed 3 Dec 2016.
- https://www.omim.org/. Accessed 3 Dec 2016.
- Gerull B, Heuser A, Wichter T, Paul M, Basson CT, McDermott DA, Lerman BB, Markowitz SM, Ellinor PT, MacRae CA, et al. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet. 2004;36(11):1162–4.View ArticlePubMedGoogle Scholar
- Dalal D, Molin LH, Piccini J, Tichnell C, James C, Bomma C, Prakasa K, Towbin JA, Marcus FI, Spevak PJ, et al. Clinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in plakophilin-2. Circulation. 2006;113(13):1641–9.View ArticlePubMedGoogle Scholar
- Watkins DA, Hendricks N, Shaboodien G, Mbele M, Parker M, Vezi BZ, Latib A, Chin A, Little F, Badri M, et al. Clinical features, survival experience, and profile of plakophylin-2 gene mutations in participants of the arrhythmogenic right ventricular cardiomyopathy registry of South Africa. Heart Rhythm. 2009;6(11 Suppl):S10–7.View ArticlePubMedGoogle Scholar
- Perrin MJ, Angaran P, Laksman Z, Zhang H, Porepa LF, Rutberg J, James C, Krahn AD, Judge DP, Calkins H, et al. Exercise testing in asymptomatic gene carriers exposes a latent electrical substrate of arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol. 2013;62(19):1772–9.View ArticlePubMedGoogle Scholar
- Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MG, Daubert JP, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J. 2010;31(7):806–14.View ArticlePubMedPubMed CentralGoogle Scholar
- Platonov PG, Calkins H, Hauer RN, Corrado D, Svendsen JH, Wichter T, Biernacka EK, Saguner AM, Te Riele AS, Zareba W. High interobserver variability in the assessment of epsilon waves: Implications for diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm. 2016;13(1):208–16.View ArticlePubMedGoogle Scholar
- Cerrone M, Lin X, Zhang M, Agullo-Pascual E, Pfenniger A, Chkourko Gusky H, Novelli V, Kim C, Tirasawadichai T, Judge DP, et al. Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype. Circulation. 2014;129(10):1092–103.View ArticlePubMedGoogle Scholar
- MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, Abecasis GR, Adams DR, Altman RB, Antonarakis SE, Ashley EA, et al. Guidelines for investigating causality of sequence variants in human disease. Nature. 2014;508(7497):469–76.View ArticlePubMedPubMed CentralGoogle Scholar
- Marston S, Montgiraud C, Munster AB, Copeland O, Choi O, Dos Remedios C, Messer AE, Ehler E, Knoll R. OBSCN mutations associated with dilated cardiomyopathy and haploinsufficiency. PLoS One. 2015;10(9):e0138568.View ArticlePubMedPubMed CentralGoogle Scholar
- Lopes LR, Murphy C, Syrris P, Dalageorgou C, McKenna WJ, Elliott PM, Plagnol V. Use of high-throughput targeted exome-sequencing to screen for copy number variation in hypertrophic cardiomyopathy. Eur J Med Genet. 2015;58(11):611–6.View ArticlePubMedGoogle Scholar