The genetic basis of HCM is more complex than previously thought: known genetic mutations are responsible for about half of the cases, while the remaining causes are unknown. Since variants have not been found to explain the presence of the disease in many patients, there are certainly other, yet unidentified genes. There is an emphasized need to discover additional genetic, epigenetic, and environmental causes that would explain the high proportion of cases of unknown etiology. For many newly reported genes, the lack of strong evidence to support a causal role in HCM creates uncertainty in the interpretation of the results. One of the major roles of genetic testing for HCM patients is better clinical surveillance of asymptomatic family members.
This study analyzed the genetic determinacy of various clinical phenotype parameters among patients with HCM. Only carriers of a single gene mutation, either MYBPC3 or MYH7 were included. Studies that performed genetic screening in large cohorts of patients with a confirmed clinical diagnosis of HCM managed to detect a pathogenic mutation in about 40-50% of patients [13, 14], suggesting that as much as half of the HCM diagnosed patients do not have known sarcomeric gene mutations.
The MYBPC3 and MYH7 mutations are the two most common mutations among HCM patients with identified sarcomeric gene mutations. A recent meta-analysis on 7675 HCM patients including a total of 51 studies performed by Sedaghat-Hamedani et al.  found that the prevalence of MYBPC3 and MYH7 gene mutations were 20% and 14%, respectively, while all the other mutations had a prevalence below 2%.
HCM is a disease of a younger age, as it is often first diagnosed before the age of 40 [14, 16]. In our study, patients’ mean age was 50 for MYBPC3 and 55 for MYH7 mutations, with no significant difference among groups. This is in contrast to previous findings, which suggest earlier onset and diagnosis of the disease for MYH7 mutation [15, 17]. Patients in our study were predominantly male, which is consistent with gender distribution across literature, where about two-thirds of HCM patients are male [13, 18, 19].
Olivotto et al.  in their study from 2005, examined gender-related differences in a multicenter population of 969 patients with HCM. Male patients had a 3:2 predominance (59%). HCM-related mortality and risk of sudden death were similar in men and women. They also pointed out that women with HCM were under-represented, older, and more symptomatic than men, and showed a higher risk of progression to advanced heart failure or death, often associated with outflow obstruction. Results from a more recent study from Jang et al.  conducted on 202 consecutive patients with non-obstructive HCM are in-line with previously mentioned. Jang et al. concluded that female patients presented with heart failure more frequently and showed a higher risk of cardiovascular events than male patients. LA volume, E/e' and LV mechanics were different between the genders, suggesting that these might contribute to greater susceptibility to heart failure in women with HCM.
Patients with MYBPC3 mutation in our study had a notable number (46%) of relatives with a confirmed HCM diagnosis. Across the literature, various rates of positive family history ranging from 25-70% have been reported [17, 18]. However, the reliability of these numbers should be taken with reserve, because family screening in patients with HCM has still not been fully implemented, despite the clear recommendations for a detailed follow-up of all adult first-degree relatives [5, 22]. New evidence suggests that screening should be performed even earlier in child age, especially in families with MYBPC3 and MYH7 mutations . Moreover, the diagnosis in relatives is often established solely on phenotypic expression (i.e. imaging methods like echocardiography and cardiac magnetic resonance), without proper genetic testing. Even in the case of performed genetic analysis, currently available methods still fail to identify more than half of patients with HCM .
Several studies have attempted to differentiate between disease severity, progression, and phenotype-based on specific mutation subclasses, but there is currently no consensus as to whether a specific phenotype or prognosis can be predicted from an MYBPC3 mutation . Mutation of the MYH7 gene is associated with an earlier onset of symptoms, more pronounced hypertrophy, and poor prognosis . The Arg453Cys mutation of MYH7 is associated with a high incidence of terminal heart failure and premature death . Several studies have found a correlation between five mutations (four in the MYH7 gene and one in the gene encoding cardiac troponin T) and high incidences of advanced cardiac death, however, these associations were not consistent with the results of other studies .
The study by Olivotto et al.  assessed the occurrence of atrial fibrillation and outcome in 480 consecutive HCM patients (age at diagnosis, 45±20 years; 61% male) during a follow-up period of 9.1±6.4 years. In their cohort, atrial fibrillation was documented in 107 patients, with a prevalence of 22%. Authors concluded that atrial fibrillation is associated with substantial risk for heart failure-related mortality, stroke, and severe functional disability, particularly in patients with outflow obstruction, those ≤50 years of age, or those developing chronic atrial fibrillation.
Atrial fibrillation tended to be more prevalent in the MYH7 group in our study. This finding is consistent with previous studies [16, 30], which reported a higher incidence of atrial fibrillation in patients with MYH7 mutation in comparison to other HCM patients. Since the development of atrial fibrillation was associated with risk factors such as LA enlargement, LV wall thickness, and LV outflow tract obstruction, these results suggest that patients with MYH7 mutation present with a more severe clinical phenotype. However, a prospective study on 237 HCM patients with a mean follow-up period of 14±10 years found no statistically significant difference in atrial fibrillation between patients with MYBPC3 and MYH7 mutations, with an incidence of 31% and 37%, respectively .
Detailed analysis of echocardiography parameters between the MYBPC3 and MYH7 groups in the present study revealed a somewhat similar phenotype expression with minor differences between the groups, although with slightly more severe disease presentation in MYH7 group. Most importantly, LV wall hypertrophy was equally expressed in both groups at the posterolateral wall and interventricular septum. Previous studies on larger groups of HCM patients that analyzed myocardial wall thickness measured by both echocardiography [15-17, 32] and cardiac magnetic resonance  also discovered no significant differences regarding LV wall thickness between MYBPC3 and MYH7 patients. The somewhat counterintuitive finding came from the Florence group , stating that LV mass index was normal in about 20% of patients with definite HCM phenotype and that increased LV mass alone should not be the parameter for establishing the clinical diagnosis of HCM. The LV mass correlated weakly with maximal wall thickness and proved more sensitive in predicting outcomes.
Heart systolic function measured through ejection fraction for LV and TAPSE for right ventricle were preserved in all study patients, with no differences between the groups. This is consistent with previous findings and current standpoint that HCM generally does not lead to systolic function deterioration. The symptoms and clinical severity are dominantly determined by the combination of diastolic dysfunction, mitral apparatus abnormalities, and LV outflow tract obstruction [34, 35]. A recent study by Miller et al.  established that patients with pathogenic, likely pathogenic or rare MYH7 variants had higher LV ejection fraction than those with MYBPC3 variants (68.8 vs. 59.1, p<0.001) and higher right ventricle ejection fraction (67.3 vs. 60.8, p = 0.018). Additionally, patients with MYBPC3 variants were more likely to have LV ejection fraction <55% (29.7% vs. 4.9%, p = 0.005).
Very interesting paper from Maron et al.  looked at whether morphological abnormalities of the mitral valve represent part of the HCM disease process. Assessment of mitral valve morphology was performed using cardiovascular magnetic resonance in 172 HCM patients (age 42±18 years; 62% men) and 172 control subjects. After careful characterization, they concluded that mitral valve leaflets are elongated independently of other disease variables, likely constituting a primary phenotypic expression of this heterogeneous disease and are an important morphological abnormality responsible for LV outflow obstruction. We wanted to further classify mitral valve abnormalities depending on the genetic basis. In this regard, the MYH7 group in our study had a significantly higher number of mitral leaflet abnormalities, mitral annulus calcifications, and the most important higher number of systolic anterior motion, contributing to the worse phenotype expression of MYH7 versus MYBPC3 gene mutations. The study of Groarke et al.  observed an increased number of mitral valve abnormalities in patients with sarcomeric gene mutations, however, they did not analyze the difference among the particular gene mutations. Waldmuller et al.  on the other hand, reported a more severe level of mitral regurgitation in patients with MYH7 mutation than in patients with MYBPC3 mutation.
Diagnosis of hereditary cardiac disorders based on genetic information is particularly challenging because of the high genetic heterogeneity and overlapping and variable nature of these clinical presentations. The clinical presentation of HCM is influenced by age, lifestyle, and presence of hypertension, among other factors. Although there is still no consensus on the exact impact of gender on HCM presentation and progression, gender influence is thought to exist and that differences in gene expression and hormonal differences affect the symptoms and clinical outcomes of HCM.
We acknowledge that the large number of operators involved in echocardiographic measurements in this multicenter study represents an unavoidable limitation. However, care was taken to standardize measurements of cardiac dimension and function by prospectively providing detailed technical instructions to all participating centers.
Finally, although the number of included patients in the study is modest, we believe that patient heterogenicity (multicenter study) confers substantial power to our data. Nevertheless, the modest size is one reason to exercise caution in extrapolating these results to the broad spectrum of hypertrophic cardiomyopathy.
It will be interesting to see, how novel therapeutical approaches tested in early clinical trials may change the symptomatic burden of HCM patients, e.g. in the SILICOFCM study .