We have described a patient with mild HCM associated with a novel, dominantly inherited, MYL3
mutation p.V79I. The mutation segregates with disease and is absent in 600 control alleles in a family in which no other mutation was identified in known HCM-associated genes. The phenotypic presentation of the p.V79I mutation is that of classical HCM with asymmetric septal hypertrophy, just as previously described for the p.A57G mutation in two unrelated Korean families [13
] but distinct from the rare midcavitary obstruction previously described in patients with p.E143K [14
], p.M149V, and p.R154H mutations [15
]. Expression was reduced and/or the disease exhibited late occurrence, as nine mutation carriers were asymptomatic and did not fulfil diagnostic criteria for HCM, and no mutation carriers below 35 years of age were affected or even borderline affected. However, four of the mutation carriers, all >35 years of age, exhibited either a borderline phenotype or ICVD. Strictly defined, the mutation has a penetrance of 10%, but as many of the carriers are below 25 years. If we define the phenotype as borderline HCM with a late onset, we can say that all mutation carriers above the age of 35 exhibit this phenotype. However, a more precise definition of the penetrance of disease will depend on followup studies. Unfortunately, it was not possible to obtain more information about the sudden deaths occurring in the two potential mutation carriers, I-1 and II-6, 4-5 decades ago. However, their existence supports that the mutation carriers are offered clinical follow-up.
The part of beta myosin containing the IQ1 motif that interacts with the N-C-loop of ELC harbours a number of HCM-associated mutations, that are, p.S782D [36
], p.S782N [35
], p.R787H [4
], p.L796F [1
], and p.A797T [37
], supporting the concept that interference with the interaction between ELC and beta myosin results in HCM. Another part of the beta myosin molecule that comes into close contact with ELC is the arginine residue at position 723 [35
], and mutations here also result in HCM, for example, p.R723G [38
] and p.R723C [39
], which further supports the concept that interference with the interaction between ELC and myosin is a pathogenetic substrate of HCM.
Homology modelling suggests that the p.V79I mutation may interfere with the interaction between ELC and myosin heavy chain, a mechanism which is believed to be the cause of disease for a number of reported mutations. Based on this evidence we find it likely that the p.V79I mutation is disease causing. However, it can not be ruled out that the mutation may only be associated with hypertrophy when other triggering conditions are present. In this case, the proband is very obese; obesity has recently been associated with a cardiac hypertrophic response in mice fed a high-fat diet through inactivation of the Foxo3a transcription factor via the Akt pathway [40
]. As the cardiac hypertrophic response in the same mouse model is associated with increased caspase activity [40
] and caspase has ELC [41
] as its primary substrate in the failing heart, obesity may aggravate the development of a hypertrophic phenotype in conditions with reduced ELC functionality. A less specific aggravation of hypertrophy through the leptin-induced cardiac hypertrophic response seen in neonatal rat cardiomyocytes phenotype could also explain that the proband is the only mutation carrier with clinical HCM [42
The finding of a clinically silent mutation with low expressivity and late onset raises the question of whether it should entail a detailed followup of mutation carriers. However, as most mutations in MYL3
have been associated with sudden death [24
], it would seem prudent to conduct a clinical followup of mutation carriers. The potential relation between a MYL3
-based genetic predisposition, the hypertrophic phenotype and obesity in the proband should also strengthen the recommendation to the proband to lose weight.