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

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

Title: Hypertrophic cardiomyopathy in myosin-binding protein C (MYBPC3) Icelandic founder mutation carriers
Author: Adalsteinsdottir, Berglind   orcid.org/0000-0002-4732-0963
Burke, Michael
Maron, Barry J
Danielsen, Ragnar
Lopez, Begoña
Díez Martínez, Domingo Francisco Javier   orcid.org/0000-0002-3414-6919
Jarolim, Petr
Seidman, Jonathan
Seidman, Christine E.
Ho, Carolyn Y
... 1 more authors Show all authors
Date: 2020-04-05
Language: English
Scope: e001220
University/Institute: Háskóli Íslands
University of Iceland
School: Heilbrigðisvísindasvið (HÍ)
School of Health Sciences (UI)
Department: Læknadeild (HÍ)
Faculty of Medicine (UI)
Series: Open Heart;7(1)
ISSN: 2053-3624
DOI: 10.1136/openhrt-2019-001220
Subject: Cardiomyopathy hypertrophic; Echocardiography; Genetics; Erfðafræði; Erfðasjúkdómar; Hjartasjúkdómar
URI: https://hdl.handle.net/20.500.11815/2383

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Adalsteinsdottir, B., Burke, M., Maron, B.J., Danielsen, R., Lopez, B., Diez, J., Jarolim, P., Seidman, J., Seidman, C.E., Ho, C.Y., Gunnarsson, G.T., 2020. Hypertrophic cardiomyopathy in myosin-binding protein C (MYBPC3) Icelandic founder mutation carriers. Open Heart 7, e001220. doi:10.1136/openhrt-2019-001220


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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