The genetic architecture of Plakophilin 2 cardiomyopathy

Annika M Dries; Anna Kirillova; Chloe M Reuter; John Garcia; Hana Zouk; Megan Hawley; Brittney Murray; Crystal Tichnell; Kalliopi Pilichou; Alexandros Protonotarios; Argelia Medeiros-Domingo; Melissa A Kelly; Aris Baras; Jodie Ingles; Christopher Semsarian; Barbara Bauce; Rudy Celeghin; Cristina Basso; Jan D H Jongbloed; Robert L Nussbaum; Birgit Funke; Marina Cerrone; Luisa Mestroni; Matthew R G Taylor; Gianfranco Sinagra; Marco Merlo; Ardan M Saguner; Perry M Elliott; Petros Syrris; J Peter van Tintelen; Regeneron Genetics Center; Cynthia A James; Christopher M Haggerty; Victoria N Parikh

doi:10.1038/s41436-021-01233-7

The genetic architecture of Plakophilin 2 cardiomyopathy

Genet Med. 2021 Oct;23(10):1961-1968. doi: 10.1038/s41436-021-01233-7. Epub 2021 Jun 12.

Authors

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Arrhythmogenic Right Ventricular Dysplasia* / genetics
Cardiomyopathies*
Genetic Testing
Humans
Phenotype
Plakophilins* / genetics

Substances

PKP2 protein, human
Plakophilins

Abstract

Publication types

MeSH terms

Substances

Grants and funding