The presence of a mutation in one of the genes suggests a worse prognosis. Mutations in the MYH7 gene, rather than in the MYBPC3 gene, were also related to a worse prognosis. This is the first work characterizing HC molecular epidemiology in the Brazilian population for the 3 most important genes.
Dominant missense pathogenic variants in cardiac myosin heavy chain cause hypertrophic cardiomyopathy (HCM), a currently incurable disorder that increases risk for stroke, heart failure and sudden cardiac death. In this study, we assessed two different genetic therapies—an adenine base editor (ABE8e) and a potent Cas9 nuclease delivered by AAV9—to prevent disease in mice carrying the heterozygous HCM pathogenic variant myosin R403Q. One dose of dual-AAV9 vectors, each carrying one half of RNA-guided ABE8e, corrected the pathogenic variant in ≥70% of ventricular cardiomyocytes and maintained durable, normal cardiac structure and function. An additional dose provided more editing in the atria but also increased bystander editing. AAV9 delivery of RNA-guided Cas9 nuclease effectively inactivated the pathogenic allele, albeit with dose-dependent toxicities, necessitating a narrow therapeutic window to maintain health. These preclinical studies demonstrate considerable potential for single-dose genetic therapies to correct or silence pathogenic variants and prevent the development of HCM.
Hypertrophic cardiomyopathy (HCM) is the most common monogenic genetic cardiac
disease, with an estimated prevalence of 1:500 in the general population. Clinically,
HCM is characterized by hypertrophy of the left ventricle (LV) walls, especially the
septum, usually asymmetric, in the absence of any cardiac or systemic disease that
leads to a secondary hypertrophy. The clinical course of the disease has a large
inter- and intrafamilial heterogeneity, ranging from mild symptoms of heart failure
late in life to the onset of sudden cardiac death at a young age and is caused by a
mutation in one of the genes that encode a protein from the sarcomere, Z-disc or
intracellular calcium modulators. Although many genes and mutations are already known
to cause HCM, the molecular pathways that lead to the phenotype are still unclear.
This review focus on the molecular mechanisms of HCM, the pathways from mutation to
clinical phenotype and how the disease's genotype correlates with phenotype.
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