Genotype-phenotype Relationships in Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is one of the most common heritable cardiovascular diseases and is the most common cause of sudden death in the young, especially the young athlete. HCM is a disease underscored by profound phenotypic and genetic heterogeneity. Since the sentinel discovery of mutations in MYH7-encoded beta myosin heavy chain as a pathogenetic basis for HCM, hundreds of mutations scattered over at least 15 genes that encode essential sarcomeric proteins have been identified.
Functional subgroups of genetic HCM and the yield of genetic testing for the two most common septal morphologies with their respective subgroup. Shown are the most important functional subgroups of genetically mediated HCM and the yield of mutations over various cohorts. Blue arrows indicate the functional relationship between the different elements. The black arrows show the yield of genetic testing for the subgroups of myofilament HCM and Z-disc HCM and their morphologic subgroups. LAMP2, lysosome-associated membrane protein 2; PLN, phospholamban; PRKAG2, AMP-activated protein kinase; SR, sarcoplasmic reticulum;RyR2, cardiac ryanodine receptor.
Recently, we have completed comprehensive mutational analysis of these 8 most common myofilament genes in the largest assembled cohort (N = 389) of unrelated patients diagnosed with HCM.(1-5) Importantly, we have discovered that i) established HCM-associated mutations are present for only 38% of these unrelated patients, ii) the two most common genotypes: myosin binding protein C-HCM and beta myosin heavy chain-HCM, were phenotypically indistinguishable, and iii) specific mutations did not carry prognostic significance among unrelated index cases.(5) Interestingly, when classified by the morphology of the heart’s ventricular septum, we found that 79% of patients with reversed septal curvature (“reverse curve-HCM”) tested positive while only 8% of patients with a sigmoidal-shaped septum (“sigmoidal-HCM”) had an HCM-causing mutation (p < 0.0001). (Figure 8)
Recent attention has been focused on proteins outside the cardiac myofilament, in particular the cardiac Z-disc, involved in the cyto-architecture and cardiac stretch sensor mechanism of the cardiomyocyte. Mutations in three such proteins, CSRP3-encoded muscle LIM protein (MLP), TCAP-encoded telethonin and the cardiac specific insert (exon 19) of VCL-encoded vinculin that yields metavinculin, have in our cohort already been associated with HCM. (6-8)
In comparison, patients with myofilament genotype negative-HCM were older, had less hypertrophy, and were less likely to have reverse curve-HCM compared to the 143 patients with myofilament-HCM.(3-5,9,10) Interestingly, in contrast to the patients with myofilament-HCM from our previous study, none of the patients with putative mutations involving the cardiac Z-disc had reverse curve-HCM by echocardiography (p < 0.0001). Instead, the majority of patients had sigmoidal-HCM. (Figure 8) and future studies are therefore directed at elucidating the genetic basis of sigmoidal HCM.
New Gene Discovery in the Pathogenesis of Hypertrophic Cardiomyopathy
To date, the Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory has discovered 5 new HCM-susceptibility genes.