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.

The genetic architecture of Plakophilin 2 cardiomyopathy

Mestroni, Luisa;Sinagra, Gianfranco;Merlo, Marco;
2021

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.
Pubblicato
https://www.sciencedirect.com/science/article/pii/S1098360021051431?via=ihub
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486657/
File in questo prodotto:
File Dimensione Formato  
1-s2.0-S1098360021051431-main.pdf

accesso aperto

Tipologia: Documento in Versione Editoriale
Licenza: Creative commons
Dimensione 1.17 MB
Formato Adobe PDF
1.17 MB Adobe PDF Visualizza/Apri
1-s2.0-S1098360021051431-mmc1.pdf

accesso aperto

Tipologia: Altro materiale allegato
Licenza: Digital Rights Management non definito
Dimensione 461.27 kB
Formato Adobe PDF
461.27 kB Adobe PDF Visualizza/Apri
1-s2.0-S1098360021051431-mmc2.pdf

accesso aperto

Tipologia: Altro materiale allegato
Licenza: Digital Rights Management non definito
Dimensione 240.04 kB
Formato Adobe PDF
240.04 kB Adobe PDF Visualizza/Apri
1-s2.0-S1098360021051431-mmc3.pdf

accesso aperto

Tipologia: Altro materiale allegato
Licenza: Digital Rights Management non definito
Dimensione 60.96 kB
Formato Adobe PDF
60.96 kB Adobe PDF Visualizza/Apri
1-s2.0-S1098360021051431-mmc4.pdf

accesso aperto

Tipologia: Altro materiale allegato
Licenza: Digital Rights Management non definito
Dimensione 1.49 MB
Formato Adobe PDF
1.49 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11368/3026288
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 2
  • ???jsp.display-item.citation.isi??? 3
social impact