Detection of a large duplication mutation in the myosin-binding protein C3 gene in a case of hypertrophic cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is a cardiovascular disease with autosomal dominant inheritance caused by mutations in genes coding for sarcomeric and/or regulatory proteins expressed in cardiomyocytes. In a small cohort of HCM patients (n=8), we searched for mutations in the two most common genes responsible for HCM and found four missense mutations in the MYH7 gene encoding cardiac β-myosin heavy chain (R204H, M493V, R719W, and R870H) and three mutations in the myosin-binding protein C3 gene (MYBPC3) including one missense (A848V) and two frameshift mutations (c.3713delTG and c.702ins26bp). The c.702ins26bp insertion resulted from the duplication of a 26-bp fragment in a 54-year-old female HCM patient presenting with clinical signs of heart failure due to diastolic dysfunction. Although such large duplications (>10 bp) in the MYBPC3 gene are very rare and have been identified only in 4 families reported so far, the identical duplication mutation was found earlier in a Dutch patient, demonstrating that it may constitute a hitherto unknown founder mutation in central European populations. This observation underscores the significance of insertions into the coding sequence of the MYBPC3 gene for the development and pathogenesis of HCM.

Keywords: Cardiac β-myosin heavy chain; DNA; Duplication; EDTA; HCM; Hg; Hypertrophic cardiomyopathy; Insertion; LMM; LV; LVEDD; MYBPC3; MYH7; Mutation; Myosin-binding protein C; PCR; SAM; TNNT2; base pair; bp; cardiac β-myosin heavy chain; dNTP; deoxynucleotide; deoxyribonucleic acid; ethylenediaminetetraacetic acid; hypertrophic cardiomyopathy; left ventricle; left ventricular end—diastolic diameter; light meromyosin domain; mercury; myosin-binding protein C3; polymerase chain reaction; systolic anterior motion; troponin t.