. 2021 Oct;23(10):1961-1968.

doi: 10.1038/s41436-021-01233-7. Epub 2021 Jun 12.

The genetic architecture of Plakophilin 2 cardiomyopathy

Annika M Dries¹, Anna Kirillova¹, Chloe M Reuter¹, John Garcia², Hana Zouk^{3

4}, Megan Hawley^{3

4}, Brittney Murray⁵, Crystal Tichnell⁵, Kalliopi Pilichou⁶, Alexandros Protonotarios⁷, Argelia Medeiros-Domingo⁸, Melissa A Kelly⁹, Aris Baras¹⁰, Jodie Ingles¹¹, Christopher Semsarian¹², Barbara Bauce⁶, Rudy Celeghin⁶, Cristina Basso⁶, Jan D H Jongbloed¹³, Robert L Nussbaum², Birgit Funke^{3

4}, Marina Cerrone¹⁴, Luisa Mestroni¹⁵, Matthew R G Taylor¹⁵, Gianfranco Sinagra¹⁶, Marco Merlo¹⁶, Ardan M Saguner¹⁷, Perry M Elliott⁷, Petros Syrris⁷, J Peter van Tintelen^{18

19}; Regeneron Genetics Center; Cynthia A James^#⁵, Christopher M Haggerty^#⁹, Victoria N Parikh^#²⁰

Affiliations

¹ Stanford Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
² Invitae, Inc, San Francisco, CA, USA.
³ Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, Cambridge, MA, USA.
⁴ Dept. Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
⁶ Dept. of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy.
⁷ Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK.
⁸ SwissDNALysis-Cardiogenetics, Dübendorf Switzerland, Zurich, Switzerland.
⁹ Geisinger, Danville, PA, USA.
¹⁰ Regeneron Genetics Center, Tarrytown, NY, USA.
¹¹ Cardio Genomics Program at Centenary Institute, The University of Sydney, Sydney, Australia.
¹² Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, University of Sydney, Sydney, Australia.
¹³ University of Groningen Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.
¹⁴ Leon H. Charney Division of Cardiology, NYU School of Medicine, New York, NY, US.
¹⁵ University of Colorado Anschutz Medical Campus, Aurora, CO, US.
¹⁶ Cardiovascular Department, Azienda Sanitaria-Universitaria Giuliano Isontina (ASUGI), Trieste, Italy.
¹⁷ Department of Cardiology, University Heart Center, University Hospital, Zurich, Switzerland.
¹⁸ Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
¹⁹ Netherlands Heart Institute, Utrecht, the Netherlands.
²⁰ Stanford Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. vparikh@stanford.edu.

^# Contributed equally.

PMID: 34120153
PMCID: PMC8486657
DOI: 10.1038/s41436-021-01233-7

The genetic architecture of Plakophilin 2 cardiomyopathy

Annika M Dries et al. Genet Med. 2021 Oct.

. 2021 Oct;23(10):1961-1968.

doi: 10.1038/s41436-021-01233-7. Epub 2021 Jun 12.

Authors

Affiliations

¹ Stanford Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
² Invitae, Inc, San Francisco, CA, USA.
³ Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, Cambridge, MA, USA.
⁴ Dept. Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
⁶ Dept. of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy.
⁷ Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK.
⁸ SwissDNALysis-Cardiogenetics, Dübendorf Switzerland, Zurich, Switzerland.
⁹ Geisinger, Danville, PA, USA.
¹⁰ Regeneron Genetics Center, Tarrytown, NY, USA.
¹¹ Cardio Genomics Program at Centenary Institute, The University of Sydney, Sydney, Australia.
¹² Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, University of Sydney, Sydney, Australia.
¹³ University of Groningen Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.
¹⁴ Leon H. Charney Division of Cardiology, NYU School of Medicine, New York, NY, US.
¹⁵ University of Colorado Anschutz Medical Campus, Aurora, CO, US.
¹⁶ Cardiovascular Department, Azienda Sanitaria-Universitaria Giuliano Isontina (ASUGI), Trieste, Italy.
¹⁷ Department of Cardiology, University Heart Center, University Hospital, Zurich, Switzerland.
¹⁸ Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
¹⁹ Netherlands Heart Institute, Utrecht, the Netherlands.
²⁰ Stanford Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. vparikh@stanford.edu.

^# Contributed equally.

PMID: 34120153
PMCID: PMC8486657
DOI: 10.1038/s41436-021-01233-7

Erratum in

Correction to: The genetic architecture of Plakophilin 2 cardiomyopathy.
Dries AM, Kirillova A, Reuter CM, Garcia J, Zouk H, Hawley M, Murray B, Tichnell C, Pilichou K, Protonotarios A, Medeiros-Domingo A, Kelly MA, Baras A, Ingles J, Semsarian C, Bauce B, Celeghin R, Basso C, Jongbloed JDH, Nussbaum RL, Funke B, Cerrone M, Mestroni L, Taylor MRG, Sinagra G, Merlo M, Saguner AM, Elliott PM, Syrris P, van Tintelen JP; Regeneron Genetics Center; James CA, Haggerty CM, Parikh VN. Dries AM, et al. Genet Med. 2021 Oct;23(10):2014. doi: 10.1038/s41436-021-01298-4. Genet Med. 2021. PMID: 34408292 Free PMC article. No abstract available.

Abstract

Purpose: The genetic architecture of Plakophilin 2 (PKP2) cardiomyopathy can inform our understanding of its variant pathogenicity and protein function.

Methods: We assess the gene-wide and regional association of truncating and missense variants in PKP2 with arrhythmogenic cardiomyopathy (ACM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) specifically. A discovery data set compares genetic testing requisitions to gnomAD. Validation is performed in a rigorously phenotyped definite ARVC cohort and non-ACM individuals in the Geisinger MyCode cohort.

Results: The etiologic fraction (EF) of ACM-related diagnoses from truncating variants in PKP2 is significant (0.85 [0.80,0.88], p < 2 × 10^-16), increases for ARVC specifically (EF = 0.96 [0.94,0.97], p < 2 × 10^-16), and is highest in definite ARVC versus non-ACM individuals (EF = 1.00 [1.00,1.00], p < 2 × 10^-16). Regions of missense variation enriched for ACM probands include known functional domains and the C-terminus, which was not previously known to contain a functional domain. No regional enrichment was identified for truncating variants.

Conclusion: This multicohort evaluation of the genetic architecture of PKP2 demonstrates the specificity of PKP2 truncating variants for ARVC within the ACM disease spectrum. We identify the PKP2 C-terminus as a potential functional domain and find that truncating variants likely cause disease irrespective of transcript position.

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Conflict of interest statement

R.L.N. is an employee and stockholder in Invitae, a consultant for Pfizer Pharmaceuticals, and consultant and stock holder for Maze Therapeutics and Genome Medical. B.M. is a consultant for MyGeneCounsel. A.B. is an employee of Regeneron Genetics Center. A.M.S. received educational grants through his institution from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, BMS/Pfizer, and Medtronic, and speaker fees from Bayer Healthcare and BMS/Pfizer. The other authors declare no competing interests.

Figures

**Fig. 1. Study design for determination of etiologic fraction (EF).**
Two independent data sets were used, one for discovery and one for validation. In the discovery data set, individuals undergoing genetic testing at Invitae, Inc. were filtered for probands carrying an arrhythmogenic cardiomyopathy (ACM)–associated diagnosis and further filtered for those carrying an arrhythmogenic right ventricular cardiomyopathy (ARVC) diagnosis specifically. Of these, EF was determined for those carrying truncating and missense variants as compared to members of the general population carrying rare *PKP2* variants (minor allele frequency [MAF] ≤ 0.0001). In the validation data set, patients with a definite diagnosis of ARVC (Johns Hopkins [JHU] and Netherlands cohorts) were included and those with a pathogenic or likely pathogenic variant in *PKP2* were compared to individuals in the Geisinger MyCode cohort with *PKP2* variants but without ACM-related diagnoses.

**Fig. 2. Study design for regional assessment of missense and truncating variant distribution.**
The discovery data set here was supplemented with genetic tests in arrhythmogenic cardiomyopathy (ACM) probands from the Laboratory for Molecular Medicine (LMM). Invitae probands and definite ARVC cohorts described in Fig. 1. The validation data set was supplemented with the addition of the International ARVC Missense Variant Cohort (N = 10 pathogenic/likely pathogenic [P/LP] *PKP2* missense variants). ^aMinor allele frequency (MAF) ≤ 3.6 × 10⁻⁵. ^bMAF ≤ 0.001. ARVC arrhythmogenic right ventricular cardiomyopathy, JHU Johns Hopkins cohort.

**Fig. 3. Regional assessment of missense variants in *PKP2* identifies potential hotspots for pathogenic variation.**
(a) Arrhythmogenic cardiomyopathy (ACM) genetic testing cohort (blue, N = 40, minor allele frequency [MAF] ≤ 3.6 × 10⁻⁵) vs. gnomAD (gray, N = 3970, MAF ≤ 0.001) Odds of inclusion of disease associated variant. (b) International ARVC Missense Variant Cohort (striped blue, MAF ≤ 3.6 × 10⁻⁵, N = 26) vs. Geisinger MyCode cohort (striped gray, N = 1678, MAF ≤ 0.001). Light blue shading indicates regional disease enrichment, false discover rate (FDR) = 0.01. ARVC arrhythmogenic right ventricular cardiomyopathy.

**Fig. 4. Regional assessment of truncating variants in PKP2 shows no association of transcript location with arrhythmogenic cardiomyopathy (ACM) phenotypes.**
(a) Clinical genetic testing cohort (red, N = 98) vs gnomAD (gray, N = 97) Odds of inclusion of disease associated variant. (No statistically significant windows at false discovery rate [FDR] 0.01. R² = 0.003, p = 0.42.) (b) Johns Hopkins (JHU)/Netherlands cohort (hatched red) vs. Geisinger cohort (hatched gray) (no statistically significant windows at FDR 0.01). ARVC arrhythmogenic right ventricular cardiomyopathy.

See this image and copyright information in PMC

References

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The genetic architecture of Plakophilin 2 cardiomyopathy

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The genetic architecture of Plakophilin 2 cardiomyopathy

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