## 4 Discussion
In cardiac amyloidosis (CA), fibrillar proteins are deposited at an extracellular level, interrupting the normal architecture and function of tissues, which then leads to the onset of phenotypic conditions such as left ventricular hypertrophy [94]. The Guidelines for the Management of Cardiomyopathies of the European Society of Cardiology (ESC) of 2023 report 57 genes associated with monogenic HCM [11; 95]. These genes, with their frequencies and strength of evidence, are schematized in Figure 2. In particular, the genes with definitive/strong evidence of HCM co-relation are MYBC3, MYH7 and TNNT2, which are reported as very commonly involved genes (>10% of tested cases); MYL2, MYL3, and TNNI3 are described as common (1-10% of tested cases) [96]. Thus, several cases are characterized by mutations in the genes encoding the structural components of the thick and thin filaments forming the cardiac muscle sarcomeres. The main genes encode for 11 sarcomeric proteins, showing >1400 mutations, affecting beta-myosin heavy chain, cardiac myosin binding protein C, cardiac troponin T, troponin I, alphatropomyosin, essential and regulatory myosin light chains, actin, alpha-myosin heavy chain, titin, and muscle LIM protein [97; 98]; frequently, the genetic test in the clinical setting reveals that most patients have mutations at the first three genes while the other genes represent a small fraction. The mutations are generally missense with a single amino acid substitution; then, small deletions or insertions are described [16; 99]. In this field, an important contribution belongs to the post-mortem genetic test, also known as the \"molecular autopsy\", which provides data on the genes involved in HCM-related SCD and, particularly, on the several variants found at each gene that (in accordance with the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Guidelines) [100] can be classified as pathogenic, likely pathogenic, of uncertain significance, likely benign, or benign. Thus, the scientific community describes the emerging value of the molecular analysis in such cases, which, furthermore, is the only tool to assess the cause of death in cases without well-defined structural heart abnormalities [2]. The results of the performed systematic review are in accordance with the previous evidence, which resulted in a major frequency of pathogenic or likely pathogenic mutation at the MYBPC3 [26; 41; 43; 44; 45; 46; 47; 48; 49; 50; 52] and MYH7 [38; 41; 43; 44; 46; 47; 48; 49; 50] genes; among the gene mutations responsible for the functional effect there were also TNNT2 [50], the other gene described as most commonly mutated in HCM and as having strong evidence of correlation; TPM1 [53], with strong evidence of HCM association, but with a frequency that was less common; and ACTN2 [51], a gene with moderate evidence of correlation and of being less commonly involved. Several different mutations were identified for each gene showing the allelic heterogeneity characterizing this disease [101]. Moreover, the review showed cases in which novel variants were found in the genes most commonly associated with HCM [44; 52], supporting the contribution of the post-mortem genetic test to the extension of existing knowledge on the genetic basis of the disease. Interestingly, in the included articles cases were described without clear heart structural alterations that revealed gene mutation with functional effects leading to the cardiomyocyte diagnosis [38; 48; 50; 52; 53]. Regarding the mechanism responsible for the HCM phenotype, several theories have been postulated, such as the \"poison polypeptide\" and the \"null alleles\" effects. These theories suggest the possibility of abnormalities on sarcomeric proteins, in which can occur the functional compromission or an impaired amount of the \"wild type\", leading to both the alteration of the mechanical function of myocytes and cellular stress [16; 101].