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

• Published in: Open Heart
• Main Authors: Adalsteinsdottir, Berglind, Burke, Michael, Maron, Barry J, Danielsen, Ragnar, Lopez, Begoña, Diez, Javier, Jarolim, Petr, Seidman, Jonathan, Seidman, Christine E, Ho, Carolyn Y, Gunnarsson, Gunnar Th
• Other Authors: 1Department of Medicine, University of Iceland, Reykjavik, Iceland. 2Division of Cardiology, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 3Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. 4Cardiology Division, Emory University School of Medicine, Atlanta, Georgia, USA. 5Hypertrophic Cardiomyopathy Center, Division of Cardiology, Tufts Medical Center, Boston, Massachusetts, USA. 6Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain. 7Carlos III Health Institute, Madrid, Spain. 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. 9Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA. 10Howard Hughes Medical Institute, Boston, Massachusetts, USA. 11Department of Medicine, Akureyri Hospital, Akureyri, Iceland.
• Format: Article in Journal/Newspaper
• Language: English
• Published: BMJ Publishing Group 2020
• Subjects: cardiomyopathy hypertrophic; echocardiography; genetics; Hjartasjúkdómar; Cardiomyopathy; Hypertrophic; Iceland
• Online Access: http://hdl.handle.net/2336/621379; https://doi.org/10.1136/openhrt-2019-001220

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Download 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. Howard ...