Genetic profile of hypertrophic cardiomyopathy in Tunisia: Is it different?

Abstract

We recently performed next generation sequencing (NGS) genetic screening in 11 consecutive and unrelated Tunisian HCM probands seen at Habib Thameur Hospital in Tunis in the first 6 months of 2014, as part of a cooperative study between our Institutions. The clinical diagnosis of HCM was made according to standard criteria. Using the Illumina platform, a panel of 12 genes was analyzed including myosin binding protein C (MYBPC3), beta-myosin heavy chain (MYH7), regulatory and essential light chains (MYL2 and MYL3), troponin-T (TNNT2), troponin-I (TNNI3), troponin-C (TNNC1), alpha-tropomyosin (TPM1), alpha-actin (ACTC1), alpha-actinin-2 (ACTN2) as well as alfa-galactosidase (GLA), 5′-AMP-activated protein (PKRAG2), transthyretin (TTR) and lysosomal-associated membrane protein-2 (LAMP2) for exclusion of phenocopies. Our preliminary data, despite limitations inherent to the small sample size, suggest that HCM in Tunisia may have a peculiar genetic background which privileges rare genes overs the classic HCM-associated MHY7 and MYBPC3 genes.

Pathogenesis of depression‐ and anxiety‐like behavior in an animal model of hypertrophic cardiomyopathy

“…1, echo confirmed structural and hemodynamic changes induced by the HCM mutation in young adult females. There were no significant differences between young control and HCM mice for HR [ t (11) = 1.277; P . 0.05], aortic ejection time (AET) [ t (10) = 1.057; P .…”

“…0.05]. HCM mice displayed trends toward higher IVRT ([ t (10) = 1.77; P = 0.1071], higher fractional shortening (FS) [ t (11) = 2.167; P = 0.053], lower MV early peak flow velocity/late atrial peak flow velocity MV E/A) [ t (10) = 1.795; P = 0.1029], and a trend toward higher ventricular volume during diastole [ t (11) = 2.14; P = 0.0556)] as compared with controls. Finally, young adult HCM mice displayed significantly higher EF [ t (11) = 2.32; P < 0.05], higher MV late atrial peak flow velocity (MV A) [ t (10) = 2.984; P < 0.05], and lower left ventricular volume during systole [ t (11) = 2.459; P < 0.05], as compared to age‐matched controls, which is indicative of diastolic dysfunction in young HCM mice.…”

“…Recently, we generated a knock‐in mouse bearing an HCM mutation in TNNC1 (gene encoding cTnC), which is expressed in the heart and slow skeletal muscles (9). Since its identification <10 yr ago (10), there have been additional reports of humans with the Ala8Val mutation in the TNNC1 gene, as well as phenotypic symptoms associated with HCM and restricted cardiomyopathy (RCM) (9, 11, 12). As has been shown for other HCM troponin‐related mutations, the cTnCAla8Val mutation in the murine heart induces cardiac interstitial fibrosis, myofibrillar disarray, left atrial enlargement, diastolic dysfunction, and an increased ejection fraction (EF) (9, 13–16).…”

Enhanced troponin I binding explains the functional changes produced by the hypertrophic cardiomyopathy mutation A8V of cardiac troponin C

“…To date, three distinct probands carrying the Ala8 to Val mutation in TnC have been reported ((7,43) and personal communication). Although one of the probands reported a parent who was also positively genotyped for the mutation, the available genetic data remain difficult to interpret.…”

“…Although one of the probands reported a parent who was also positively genotyped for the mutation, the available genetic data remain difficult to interpret. In one clinical report, the mutation arose de novo ; in another report, the proband carried two mutations in different sarcomeric proteins (7,43). The functional characterization is crucial to ascertain whether the A8V mutation in TnC is a true pathogenic variant and how it exerts its negative effect on muscle regulation.…”