## 4 Discussion
This may converge in the activation of the stress-response signal, determining the activation of myocyte transcriptional pathways and the compensatory tissue alterations (hypertrophy, disarray, and fibrosis) [102; 103]. Moreover, to explain the SCD in cases without cardiac morpho-structural alterations, some authors suggested that the functional abnormalities of myocytes due to the sarcomere mutations  
Figure 2: Frequency and strength of evidence of genes associated with HCM [11]; most common: >10% of the cases; common: 1–10% of the cases; less common: <1% of the cases; in red: genes associated with syndromes in which cardiomyopathy is not expected to occur as the only or presenting feature of the disease (ABCC9: [PERSON] syndrome; BAG3: Myofibrillar myopathy; CAV3: Caveolinopathy; COX15: Leigh syndrome; CRYAB: Alpha-B crystallinity; FXN: Friedrich ataxia; GAA: Pompe disease; LDB3: Myofibrillar myopathy; SLC25A4: Mitochondrial disease); in blue: genes associated with syndromes in which cardiomyopathy may be the only or presenting feature of the disease (CACNA1C: Timothy syndrome; DES: Desminopathy; FHL1: Emery–Drefiuss MD; FLNC: Myofibrillar myopathy; GLA: Anderson–Fabry disease; LAMP2: Danon disease; PRKAG2: PRKAG2 cardiomyopathy; PTPN11-RAF1-RIT1: Noonan syndrome; TTR: transthyretin amyloidosis). may occur before the onset of gross myocardial hypertrophy, theoretically determining an increased risk of arrhythmia [50; 104]. HCM research is also focused on the analysis of genotype-phenotype correlation with evidence belonging to both clinical and forensic/post-mortem studies; however, there are cases in which pathogenic or presumed pathogenic mutation were not identified in the subject with the HCM phenotype (for instance, in the clinical setting the identification of causal mutation has been reported in about 30% to 40% of patients) [98]. It was reported that about 5% to 7% of patients with HCM with \(\geq\)2 mutations seem to show a more severe phenotype (the so called \"gene-dose theory\"), as did the homozygous subjects [105; 106]. The data obtained from the comparisons between the specific mutated genes showed variable results; for instance: the comparison between MYBPC3 and MYH7 did not reveal significant differences in cardiomyopathy phenotypical expression [107; 108]; the comparison between the genes encoding the sarcomere thin filament (TNN2, TNNT3, TMP1 and ACTC) and the thick filament (MYBPC3, MYH7 and MYL2) concluded that there was an increased risk of advanced LV dysfunction and heart failure in cases with thin filament mutations, and an equal arrhythmic risk [109]. On the other hand, there are reports supporting the correlation of a specific variant in gene mutations and a more severe phenotype; p.Arg470 Gln and p.Thr1046 Met mutations in MYBPC3 have been reported to have an amount of myocyte disarray greater than 10%, even if two cases with the same variant (p.Thr1046 Met) differed either for heart weight, percentage and distribution of disarray, or LV thickness [47]; p.Gly278 GlufsTer22 and p.Phe295 SerfsTer5 in MYBPC3 have been associated with higher heart weight-to-BMI ratios and death under the age of 40 [26]; Arg453 Cys mutation in MYH7 has been described in an increased incidence of end-stage heart failure and premature death [110]. Despite several studies suggesting the association between specific gene mutations and reduced survival, this is not always true because of the great variation in phenotype expression observed in subjects having the same genetic variant. There is no evidence on genotype-phenotype correlation that is strong enough to provide information that is potentially useful for the patient care, especially regarding a phenotype prediction and the clinical outcomes. For this reason, the implementation of a model integrating a broad genetic profile and the deep clinical/morphstructural phenotyping may be the only tool for achieving effective findings and for implementing the patient prognostic perspective from the forensic point of view.