Article Text
Abstract
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.
- cardiomyopathy hypertrophic
- genetics
- echocardiography
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Footnotes
CES, CYH and GTG are joint senior authors.
Contributors Conceptualisation: BA, GTG, CYH, CES, JGS and BJM. Data curation: BA and GTG. Formal analysis: BA, GTG and JGS. Funding: GTG, CYH, CES, JGS and BA. Investigation: BA, GTG, CYH, CES, JGS, MAB, BL, JD and PJ. Methodology: BA, GTG, CYH, CES and JGS. Project administration: BA, GTG, CYH, CES and JGS. Resources: GTG, CYH, CES, JGS, BA and RD. Supervision: GTG, CYH, CES and JGS. Validation: BA, GTG, CYH, CES and JGS. Visualisation: BA, GTG, CYH, CES and JGS. Writing: original draft: BA, GTG, CYH and CES. Writing: review and editing: All authors. BA and GTG are responsible for the overall content as guarantors.
Funding This study was supported by the Howard Hughes Medical Institute (CES), the National Institutes of Health (5HL084553: CES, JGS; 1P20HL101408: CYH; 1P50HL112349: CYH), Akureyri Hospital Research Fund (GTG), Landspitali–The National University Hospital of Iceland Research Fund (BA), the Icelandic Cardiac Society Research Fund (GTG).
Competing interests CES and JGS are founders and own shares in Myokardia Inc., a startup company that is developing therapeutics that target the sarcomere. CYH is a consultant for Myokardia, Inc. Myokardia had no involvement in this study.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request, including deidentified individual participant data.