A Novel HRAS Mutation Independently Contributes to Left Ventricular Hypertrophy in a Family with a Known MYH7 Mutation.

Several genetic conditions can lead to left ventricular hypertrophy (LVH). Among them, hypertrophic cardiomyopathy (HCM), caused by mutations in sarcomere genes, is the most common inherited cardiac disease. Instead, RASopathies, a rare class of disorders characterized by neuro-cardio-facial-cutaneous abnormalities and sometimes presenting with LVH, are caused by mutations in the RAS-MAPK pathway. We report on a 62-years-old male who presented isolated severe obstructive LVH but did not carry the sarcomere mutation previously identified in his affected relatives. By exome sequencing, we detected a novel mutation in HRAS gene (NM_005343.2:p.Arg68Trp), present also in the proband's daughter, who showed mild LVH and severe intellectual disability. The cardiac phenotype was indistinguishable between family members carrying either mutation. In silico studies suggested that the mutated HRAS protein is constitutionally activated. Consistently, functional characterization in vitro confirmed elevated HRAS-GTP accumulation and downstream RAS-MAPK pathway activation that are known to drive cell proliferation in LVH. Our study emphasizes the role of RAS signaling in cardiac hypertrophy and highlights the complexity in differential diagnosis of RASopathies. In fact, the mild features of RASopathy and the recurrence of sarcomeric HCM in this family delayed the correct diagnosis until comprehensive genetic testing was performed.

Hepatitis C virus (HCV) coinfection in a cohort of HIV positive long-term non-progressors: possible protective effect of infecting HCV genotype on HIV disease progression.

BACKGROUND AND OBJECTIVE: Hepatitis C virus (HCV) infection is frequent in HIV-positive subjects. We evaluated the potential impact of HCV coinfection and other determinants on HIV disease progression in a cohort of long-term non-progressors (LTNPs). STUDY DESIGN: We studied immunological and virological factors in a cohort of 49 LTNPs, 23 of whom progressed during the follow-up (late progressors; LPs). RESULTS: HCV coinfection was detected in 19/26 LTNPs and 15/23 LPs. Univariate analysis showed that HIV viral load was associated with disease progression (P=0.04), and time-to-event analysis indicated that HCV genotype 1 significantly correlated with LTNP status (P=0.031). At multivariate analysis, HIV viremia at study entry remained independently associated with LTNP status (P=0.049). When the most represented genotypes (1 and 3a) were considered in the model, genotype 3a infection (P=0.034) and gender (P=0.035) emerged as independent variables related to HIV disease progression, whereas HIV viral load disappeared. CONCLUSIONS: In addition to HIV viremia, coinfection with different HCV genotypes and gender may affect LTNP status.