Genetic Spectrum, Clinical Characteristics, and Molecular Pathogenesis of Hypertrophic Cardiomyopathy Requiring Heart Transplantation

Hypertrophic cardiomyopathy (HCM) progressing to end-stage heart failure and heart transplantation (HT) is a rare clinical scenario with an insufficiently explored genetic background. In this single-center retrospective cohort study, we aimed to characterize the genetic spectrum, variants of HCM adverse remodeling, and aspects of molecular pathogenesis of this subgroup. The study included 14 patients (9 females), among whom 10 developed a dilated/hypokinetic phenotype and 4 a restrictive phenotype. In 13 patients (93%), at least one pathogenic or likely pathogenic genetic variant was identified. Dilated remodeling/hypokinesis was associated with loss-of-function variants in <i>LAMP2</i> (3) in females, <i>ALPK3homo</i> (1), <i>MYH7</i> (1), <i>MYBPC3</i> (1), a heterozygous missense variant in <i>TRIM63</i> (1), <i>FLNCtv</i> (1), <i>TTNtv</i> (2). For the latter two, electrophoretic analysis of titin isoform composition and protein content in myocardial fragments from explanted hearts confirmed the functional significance of <i>TTN</i> gene variants. The restrictive phenotype in the adult group was associated with carriage of multiple pathogenic sarcomere gene variants: <i>MYL3homo</i> (1), <i>MYBPC3</i>+<i>TPM1</i> (1), an <i>MYH7</i> converter domain variant (1), and, in one child, with a <i>TNNT2</i> variant. This findings support HCM progressing to HT is characterized by a higher frequency of variants in non-sarcomeric genes and Danon disease compared to the general HCM cohort.