Clinical Features and Outcome of Hypertrophic Cardiomyopathy Associated With Triple Sarcomere Protein Gene Mutations

In the present study, we provide the first description of the clinical profile associated with triple sarcomere gene mutations in a large HCM cohort from three referral institutions. A total of 488 unrelated index HCM patients underwent screening for myofilament gene mutations by direct DNA sequencing of eight myofilament-encoding genes for myosin binding protein C (MYBPC3), beta-myosin heavy chain (MYH7), regulatory and essential light chains (MYL2,MYL3), troponin-T (TNNT2), troponin-I (TNNI3), alpha-tropomyosin (TPM1) and actin (ACTC). Of the 488 index patients, 4 (0.8%) harboured triple sarcomere gene mutations, as follows: MYH7-R869H, MYBPC3- E258K and TNNI3-A86fs in a 32-year old female; MYH7-R723C, MYH7-E1455X and MYBPC3-E165D in a 46-year old male; MYBPC3-insC1065, MYBPC3-P371R and MYH7-R869H in a 45-year old female; and MYBPC3-Q969X, MYBPC3-R668H, MYH7-R1079Q in a 50-year old female. All patients had significant risk factors for sudden cardiac death (SCD) (n=3) or a history of resuscitated cardiac arrest (n=1), resulting in the insertion of implantable cardioverter-defibrillators (ICD) which appropriately intervened in two patients. Moreover, three out of four had a severe phenotype with progression to end-stage HCM by the fourth decade, requiring cardiac transplantation (n=1) or bivertricular pacing (n=2). The fourth patient, however, had clinically mild disease. These findings reinforce the unfavourable significance of complex genotypes in patients with HCM.