Phenotype-genotype discordance in patients with hypertrophic cardiomyopathy: clinical and echocardiographic correlates

Abstract Introduction Hypertrophic cardiomyopathy (HCMP) is a common genetic disorder characterized by asymmetric septal hypertrophy (ASH) on echocardiography. However, the diagnosis of HCMP can be challenging, as not all patients with ASH have a pathogenic genetic mutation. Purpose The aim of this study was to investigate the clinical and echocardiographic correlates of phenotype-genotype discordance in patients with HCMP feature in clinical field. Methods The study included 28 patients with an HCM phenotype confirmed by echocardiography with ASH. The patients underwent whole exome sequencing (WES) for genetic testing, were divided into two groups based on the presence (concordance group) or absence (discordance group) of a pathogenic mutation on WES. Echocardiographic parameters, including interventricular septum thickness at end-diastole (IVSd), interventricular septum thickness at end-systole (IVSs), posterior wall thickness at end-diastole (PWd), posterior wall thickness at end-systole (PWs), and global average strain (GAS), were compared between the two groups. Receiver operating characteristic (ROC) curve analysis was performed to identify the echocardiographic parameters that could predict genotype discordance. Results Only 11 out of 28 patients (39%) showed an HCM genotype result by WES. The discordance group (n=17) showed significantly higher PWd (p=0.001), PWs (p=0.005) and lower left ventricle mass (p=0.024) than the concordance group (n=11). The discordance group also showed a decreased tendency in GAS compared to the concordant group. In ROC curve analysis, PWd could reversely predict the phenotype-genotype concordance with a sensitivity of 81.8% and specificity of 71.4% (area under the curve=0.841, p=0.004). Conclusion The study suggests that there is a high discordance rate between phenotype and genotype in patients with HCM. Echocardiographic parameters, especially PWd and PWs, may be useful in predicting phenotype-genotype discordance. These findings have important implications for clinical management and genetic counseling in patients with suspected HCMP.