TY - JOUR
T1 - The arrhythmogenic cardiomyopathy phenotype associated with PKP2 c.1211dup variant
AU - Bos, Thomas A.
AU - Piers, Sebastiaan R. D.
AU - Wessels, Marja W.
AU - Houweling, Arjan C.
AU - Bökenkamp, Regina
AU - Bootsma, Marianne
AU - Bosman, Laurens P.
AU - Evertz, Reinder
AU - Hellebrekers, Debby M. E. I.
AU - Hoedemaekers, Yvonne M.
AU - Knijnenburg, Jeroen
AU - Lekanne Deprez, Ronald
AU - van Mil, Anneke M.
AU - te Riele, Anneline S. J. M.
AU - van Slegtenhorst, Marjon A.
AU - Wilde, Arthur A. M.
AU - Yap, Sing-Chien
AU - Dooijes, Dennis
AU - Koopmann, Tamara T.
AU - van Tintelen, J. Peter
AU - Barge-Schaapveld, Daniela Q. C. M.
AU - European Reference Network for rare, low prevalence and complex diseases of the heart: ERN GUARD-Heart
AU - Houweling, Arjan C.
AU - Lekanne Deprez, Ronald
AU - te Riele, Anneline S. J. M.
AU - Wilde, Arthur A. M.
AU - van Tintelen, J. Peter
N1 - Funding Information: The Netherlands ACM Registry receives funding from the Netherlands Cardiovascular Research Initiative. Publisher Copyright: © 2023, The Author(s).
PY - 2023/8/1
Y1 - 2023/8/1
N2 - Background: The arrhythmogenic cardiomyopathy (ACM) phenotype, with life-threatening ventricular arrhythmias and heart failure, varies according to genetic aetiology. We aimed to characterise the phenotype associated with the variant c.1211dup (p.Val406Serfs*4) in the plakophilin‑2 gene (PKP2) and compare it with previously reported Dutch PKP2 founder variants. Methods: Clinical data were collected retrospectively from medical records of 106 PKP2 c.1211dup heterozygous carriers. Using data from the Netherlands ACM Registry, c.1211dup was compared with 3 other truncating PKP2 variants (c.235C > T (p.Arg79*), c.397C > T (p.Gln133*) and c.2489+1G > A (p.?)). Results: Of the 106 carriers, 47 (44%) were diagnosed with ACM, at a mean age of 41 years. By the end of follow-up, 29 (27%) had experienced sustained ventricular arrhythmias and 12 (11%) had developed heart failure, with male carriers showing significantly higher risks than females on these endpoints (p < 0.05). Based on available cardiac magnetic resonance imaging and echocardiographic data, 46% of the carriers showed either right ventricular dilatation and/or dysfunction, whereas a substantial minority (37%) had some form of left ventricular involvement. Both geographical distribution of carriers and haplotype analysis suggested PKP2 c.1211dup to be a founder variant originating from the South-Western coast of the Netherlands. Finally, a Cox proportional hazards model suggested significant differences in ventricular arrhythmia–free survival between 4 PKP2 founder variants, including c.1211dup. Conclusions: The PKP2 c.1211dup variant is a Dutch founder variant associated with a typical right-dominant ACM phenotype, but also left ventricular involvement, and a possibly more severe phenotype than other Dutch PKP2 founder variants.
AB - Background: The arrhythmogenic cardiomyopathy (ACM) phenotype, with life-threatening ventricular arrhythmias and heart failure, varies according to genetic aetiology. We aimed to characterise the phenotype associated with the variant c.1211dup (p.Val406Serfs*4) in the plakophilin‑2 gene (PKP2) and compare it with previously reported Dutch PKP2 founder variants. Methods: Clinical data were collected retrospectively from medical records of 106 PKP2 c.1211dup heterozygous carriers. Using data from the Netherlands ACM Registry, c.1211dup was compared with 3 other truncating PKP2 variants (c.235C > T (p.Arg79*), c.397C > T (p.Gln133*) and c.2489+1G > A (p.?)). Results: Of the 106 carriers, 47 (44%) were diagnosed with ACM, at a mean age of 41 years. By the end of follow-up, 29 (27%) had experienced sustained ventricular arrhythmias and 12 (11%) had developed heart failure, with male carriers showing significantly higher risks than females on these endpoints (p < 0.05). Based on available cardiac magnetic resonance imaging and echocardiographic data, 46% of the carriers showed either right ventricular dilatation and/or dysfunction, whereas a substantial minority (37%) had some form of left ventricular involvement. Both geographical distribution of carriers and haplotype analysis suggested PKP2 c.1211dup to be a founder variant originating from the South-Western coast of the Netherlands. Finally, a Cox proportional hazards model suggested significant differences in ventricular arrhythmia–free survival between 4 PKP2 founder variants, including c.1211dup. Conclusions: The PKP2 c.1211dup variant is a Dutch founder variant associated with a typical right-dominant ACM phenotype, but also left ventricular involvement, and a possibly more severe phenotype than other Dutch PKP2 founder variants.
KW - Arrhythmogenic Cardiomyopathy
KW - Founder mutation
KW - Genetics
KW - Plakophilin‑2
UR - http://www.scopus.com/inward/record.url?scp=85165433891&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s12471-023-01791-2
DO - https://doi.org/10.1007/s12471-023-01791-2
M3 - Article
C2 - 37505369
SN - 1568-5888
VL - 31
SP - 315
EP - 323
JO - Netherlands heart journal
JF - Netherlands heart journal
IS - 7-8
ER -