The genetic architecture of Plakophilin 2 cardiomyopathy.

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

Journal

Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831

Informations de publication

Date de publication:
10 2021
Historique:
received: 08 02 2021
accepted: 17 05 2021
revised: 16 05 2021
pubmed: 14 6 2021
medline: 26 10 2021
entrez: 13 6 2021
Statut: ppublish

Résumé

The genetic architecture of Plakophilin 2 (PKP2) cardiomyopathy can inform our understanding of its variant pathogenicity and protein function. 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. The etiologic fraction (EF) of ACM-related diagnoses from truncating variants in PKP2 is significant (0.85 [0.80,0.88], p < 2 × 10 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.

Identifiants

DOI: 10.1038/s41436-021-01233-7 PMID: 34120153 PMC: PMC8486657
pubmed: 34120153
doi: 10.1038/s41436-021-01233-7
pii: S1098-3600(21)05143-1
pmc: PMC8486657
mid: NIHMS1717834
doi:

Substances chimiques

PKP2 protein, human 0
Plakophilins 0

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

1961-1968

Subventions

Organisme : NHLBI NIH HHS
ID : R01 HL141901
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL147064
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL109209
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006542
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL069071
Pays : United States
Organisme : NHLBI NIH HHS
ID : K08 HL143185
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001082
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL116906
Pays : United States

Commentaires et corrections

Type : ErratumIn

Informations de copyright

© 2021. The Author(s).

Références

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Auteurs

Annika M Dries (AM)

Stanford Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.

Anna Kirillova (A)

Stanford Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.

Chloe M Reuter (CM)

Stanford Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.

John Garcia (J)

Invitae, Inc, San Francisco, CA, USA.

Hana Zouk (H)

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, Cambridge, MA, USA.
Dept. Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Megan Hawley (M)

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, Cambridge, MA, USA.
Dept. Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Brittney Murray (B)

Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.

Crystal Tichnell (C)

Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.

Kalliopi Pilichou (K)

Dept. of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy.

Alexandros Protonotarios (A)

Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK.

Argelia Medeiros-Domingo (A)

SwissDNALysis-Cardiogenetics, Dübendorf Switzerland, Zurich, Switzerland.

Melissa A Kelly (MA)

Geisinger, Danville, PA, USA.

Aris Baras (A)

Regeneron Genetics Center, Tarrytown, NY, USA.

Jodie Ingles (J)

Cardio Genomics Program at Centenary Institute, The University of Sydney, Sydney, Australia.

Christopher Semsarian (C)

Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, University of Sydney, Sydney, Australia.

Barbara Bauce (B)

Dept. of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy.

Rudy Celeghin (R)

Dept. of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy.

Cristina Basso (C)

Dept. of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy.

Jan D H Jongbloed (JDH)

University of Groningen Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.

Robert L Nussbaum (RL)

Invitae, Inc, San Francisco, CA, USA.

Birgit Funke (B)

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, Cambridge, MA, USA.
Dept. Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Marina Cerrone (M)

Leon H. Charney Division of Cardiology, NYU School of Medicine, New York, NY, US.

Luisa Mestroni (L)

University of Colorado Anschutz Medical Campus, Aurora, CO, US.

Matthew R G Taylor (MRG)

University of Colorado Anschutz Medical Campus, Aurora, CO, US.

Gianfranco Sinagra (G)

Cardiovascular Department, Azienda Sanitaria-Universitaria Giuliano Isontina (ASUGI), Trieste, Italy.

Marco Merlo (M)

Cardiovascular Department, Azienda Sanitaria-Universitaria Giuliano Isontina (ASUGI), Trieste, Italy.

Ardan M Saguner (AM)

Department of Cardiology, University Heart Center, University Hospital, Zurich, Switzerland.

Perry M Elliott (PM)

Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK.

Petros Syrris (P)

Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK.

J Peter van Tintelen (JP)

Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
Netherlands Heart Institute, Utrecht, the Netherlands.

Cynthia A James (CA)

Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.

Christopher M Haggerty (CM)

Geisinger, Danville, PA, USA.

Victoria N Parikh (VN)

Stanford Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. vparikh@stanford.edu.
ORCID: 0000-0002-5138-5559

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Classifications MeSH

questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Malformations › Malformations cardiovasculaires › Cardiopathies congénitales › Dysplasie ventriculaire droite arythmogène › The genetic architecture of Plakophilin 2...
questionsmedicales.fr › Maladies cardiovasculaires › Cardiopathies › Cardiomyopathies › The genetic architecture of Plakophilin 2...
questionsmedicales.fr › Établissements, main d'oeuvre et services de soins de santé › Services de santé › Services de médecine préventive › Services de diagnostic › Dépistage génétique › The genetic architecture of Plakophilin 2...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The genetic architecture of Plakophilin 2...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › The genetic architecture of Plakophilin 2...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines du cytosquelette › Plakophilines › The genetic architecture of Plakophilin 2...