TY - JOUR
T1 - MYH7 p.(Arg1712Gln) is pathogenic founder variant causing hypertrophic cardiomyopathy with overall relatively delayed onset
AU - Marsili, Luisa
AU - van Lint, Freyja H. M.
AU - Russo, Francesco
AU - van Spaendonck-Zwarts, Karin Y.
AU - Ader, Flavie
AU - Bichon, Marie-Line
AU - Faivre, Laurence
AU - Houweling, Arjan C.
AU - Isidor, Bertrand
AU - Lekanne Deprez, Ronald H.
AU - Cox, Moniek G. P. J.
AU - Wilde, Arthur A. M.
AU - Mazel, Benoit
AU - Mercier, Sandra
AU - Dooijes, Dennis
AU - Millat, Gilles
AU - The European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart
AU - Nguyen, Karine
AU - Post, Jan G.
AU - Richard, Pascale
AU - van de Beek, Irma
AU - Vermeer, Alexa M. C.
AU - Boven, Ludolf
AU - Jongbloed, Jan D. H.
AU - van Tintelen, J. Peter
AU - Marsili, Luisa
AU - van Lint, Freyja H. M.
AU - van Tintelen, J. Peter
AU - Houweling, Arjan C.
AU - Lekanne Deprez, Ronald H.
AU - Wilde, Arthur A. M.
AU - Dooijes, Dennis
AU - Post, Jan G.
AU - van de Beek, Irma
AU - Vermeer, Alexa M. C.
AU - van Spaendonck-Zwarts, Karin Y.
AU - Ader, Flavie
AU - Richard, Pascale
AU - Isidor, Bertrand
AU - Bichon, Marie-Line
AU - Mercier, Sandra
N1 - Funding Information: This work was supported by the Netherlands Cardiovascular Research Initiative, an initiative supported by the Dutch Heart Foundation (Hartstichting; CardioVasculair Onderzoek Nederland (CVON) projects: PREDICT2 2018-30, DOSIS 2014-40, DOUBLE-DOSE 2020B005). Publisher Copyright: © 2023, The Author(s).
PY - 2023/8/1
Y1 - 2023/8/1
N2 - Introduction: The MYH7 c.5135G > A p.(Arg1712Gln) variant has been identified in several patients worldwide and is classified as pathogenic in the ClinVar database. We aimed to delineate its associated phenotype and evaluate a potential founder effect. Methods: We retrospectively collected clinical and genetic data of 22 probands and 74 family members from an international cohort. Results: In total, 53 individuals carried the MYH7 p.(Arg1712Gln) variant, of whom 38 (72%) were diagnosed with hypertrophic cardiomyopathy (HCM). Mean age at HCM diagnosis was 48.8 years (standard deviation: 18.1; range: 8–74). The clinical presentation ranged from asymptomatic HCM to arrhythmias (atrial fibrillation and malignant ventricular arrhythmias). Aborted sudden cardiac death (SCD) leading to the diagnosis of HCM occurred in one proband at the age of 68 years, and a family history of SCD was reported by 39% (5/13) probands. Neither heart failure deaths nor heart transplants were reported. Women had a generally later-onset disease, with 14% of female carriers diagnosed with HCM at age 50 years compared with 54% of male carriers. In both sexes, the disease was fully penetrant by age 75 years. Haplotypes were reconstructed for 35 patients and showed a founder effect in a subset of patients. Conclusion: MYH7 p.(Arg1712Gln) is a pathogenic founder variant with a consistent HCM phenotype that may present with delayed penetrance. This suggested that clinical follow-up should be pursued after the seventh decade in healthy carriers and that longer intervals between screening may be justified in healthy women < 30 years.
AB - Introduction: The MYH7 c.5135G > A p.(Arg1712Gln) variant has been identified in several patients worldwide and is classified as pathogenic in the ClinVar database. We aimed to delineate its associated phenotype and evaluate a potential founder effect. Methods: We retrospectively collected clinical and genetic data of 22 probands and 74 family members from an international cohort. Results: In total, 53 individuals carried the MYH7 p.(Arg1712Gln) variant, of whom 38 (72%) were diagnosed with hypertrophic cardiomyopathy (HCM). Mean age at HCM diagnosis was 48.8 years (standard deviation: 18.1; range: 8–74). The clinical presentation ranged from asymptomatic HCM to arrhythmias (atrial fibrillation and malignant ventricular arrhythmias). Aborted sudden cardiac death (SCD) leading to the diagnosis of HCM occurred in one proband at the age of 68 years, and a family history of SCD was reported by 39% (5/13) probands. Neither heart failure deaths nor heart transplants were reported. Women had a generally later-onset disease, with 14% of female carriers diagnosed with HCM at age 50 years compared with 54% of male carriers. In both sexes, the disease was fully penetrant by age 75 years. Haplotypes were reconstructed for 35 patients and showed a founder effect in a subset of patients. Conclusion: MYH7 p.(Arg1712Gln) is a pathogenic founder variant with a consistent HCM phenotype that may present with delayed penetrance. This suggested that clinical follow-up should be pursued after the seventh decade in healthy carriers and that longer intervals between screening may be justified in healthy women < 30 years.
KW - Cardiomyopathy
KW - Founder mutation
KW - Hypertrophic cardiomyopathy
KW - MYH7
KW - Myosin heavy chain 7
UR - http://www.scopus.com/inward/record.url?scp=85165483085&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s12471-023-01798-9
DO - https://doi.org/10.1007/s12471-023-01798-9
M3 - Article
C2 - 37488328
SN - 1568-5888
VL - 31
SP - 300
EP - 307
JO - Netherlands heart journal
JF - Netherlands heart journal
IS - 7-8
ER -