Hypertrophic cardiomyopathy in myosin-binding protein C (MYBPC3) Icelandic founder mutation carriers

Objective: The myosin-binding protein C (MYBPC3) c.927-2A>G founder mutation accounts for >90% of sarcomeric hypertrophic cardiomyopathy (HCM) in Iceland. This cross-sectional observational study explored the penetrance and phenotypic burden among carriers of this single, prevalent founder mut...

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Autores: Adalsteinsdottir, B. (Berglind)|||/items/c432324c-4ba4-40b1-af86-989f206435d5, Burke, M. (Michael)|||/items/bb040825-2272-474a-8b9a-5552d69641ff, Maron, B.J. (Barry J.)|||/items/bf1bb31c-73bb-41fc-a0c8-b5952928dd33, Danielsen, R. (Ragnar)|||/items/78b1f9ab-0de1-49ab-82fd-18b0e22af6c4, Lopez-Salazar, M.B. (María Begoña)|||/items/153e0e37-14b0-403e-afab-8af00c4edde0, Diez, J. (Javier)|||/items/adeda0be-cebc-4240-899c-ab26f05dea9c, Jarolim, P. (Petr)|||/items/e272c93c-1d87-4df9-85be-8fa4a5997483, Seidman, J.G. (J.G.)|||/items/bc25652d-4970-4d4b-a08d-0060b6041f0b, Seidman, C.E. (Christine E.)|||/items/692dc8d4-4d8a-496c-bcef-df58a630bd49, Ho, C.Y. (Carolyn Y.)|||/items/580b53c3-2426-46ac-9a8a-24d052e9db36, Gunnarsson, G.T. (Gunnar Th)|||/items/a75978e0-8814-461c-bb87-53afedea7e86
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/65191
Acceso en línea:https://hdl.handle.net/10171/65191
Access Level:acceso abierto
Palabra clave:Cardiomyopathy hypertrophic
Iceland
Myosin-binding protein C (MYBPC3)
Echocardiography
Genetics
Descripción
Sumario:Objective: The myosin-binding protein C (MYBPC3) c.927-2A>G founder mutation accounts for >90% of sarcomeric hypertrophic cardiomyopathy (HCM) in Iceland. This cross-sectional observational study explored the penetrance and phenotypic burden among carriers of this single, prevalent founder mutation. Methods: We studied 60 probands with HCM caused by MYBPC3 c.927-2A>G and 225 first-degree relatives. All participants underwent comprehensive clinical evaluation and relatives were genotyped. Results: Genetic and clinical evaluation of relatives identified 49 genotype-positive (G+) relatives with left ventricular hypertrophy (G+/LVH+), 59 G+without LVH (G+/LVH−) and 117 genotype-negative relatives (unaffected). Compared with HCM probands, G+/ LVH+ relatives were older at HCM diagnosis, had less LVH, a less prevalent diastolic dysfunction, fewer ECG abnormalities, lower serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I levels, and fewer symptoms. The penetrance of HCM was influenced by age and sex; specifically, LVH was present in 39% of G+males but only 9% of G+females under age 40 years (p=0.015), versus 86% and 83%, respectively, after age 60 (p=0.89). G+/LVH− subjects had normal wall thicknesses, diastolic function and NT-proBNP levels, but subtle changes in LV geometry and more ECG abnormalities than their unaffected relatives. Conclusions: Phenotypic expression of the Icelandic MYBPC3 founder mutation varies by age, sex and proband status. Men are more likely to have LVH at a younger age, and disease manifestations were more prominent in probands than in relatives identified via family screening. G+/LVH− individuals had subtle clinical differences from unaffected relatives well into adulthood, indicating subclinical phenotypic expression of the pathogenic mutation.

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