Digenic inheritance of mutations in the cardiac troponin ( TNNT2 ) and cardiac beta myosin heavy chain ( MYH7 ) as the cause of severe dilated cardiomyopathy

Abstract

Familial dilated cardiomyopathy (DCM) is characterized by ventricular dilation and depressed myocardial performance. It is a genetically heterogeneous disorder associated with mutations in over 60 genes. We carried out whole exome sequencing in combination with cardiomyopathy-related gene-filtering on two affected family members to identify the possible causative mutation in a consanguineous Iranian family with DCM. Two novel variants in cardiomyopathy-related genes were identified: c.247 A > C; p.N83H in the Troponin T Type 2 gene (TNNT2) and c.2863G > A; p.D955N in the Myosin Heavy Polypeptide 7 gene (MYH7). Sanger sequencing and co-segregation analysis in the remaining family members supported the coexistence of these digenic mutations in affected members of the family. Carriers of either variant alone were asymptomatic. In summary, we find that digenic inheritance of two novel variants in DCM related genes is associated with a severe form of DCM. Exome sequencing has been shown to be very useful in identifying pathogenic mutations in cardiomyopathy families, and this report emphasizes the importance of comprehensive screening of DCM related genes, even after the identification of a single disease-causing mutation.

Digenic inheritance and genetic modifiers

“…Affected members carried both mutations whereas the carriers of either mutation were asymptomatic. The authors used Whole Exome Sequencing (WES) followed by targeted filtered analysis of the 60 or so genes, normally mutated in this highly heterogeneous condition …”

“…The authors used Whole Exome Sequencing (WES) followed by targeted filtered analysis of the 60 or so genes, normally mutated in this highly heterogeneous condition. 48 A report of DI serving as an exemplar of the vulnerability of complex protein structures, is CANDLE/PRAAS, a form of proteasome-associated autoinflammatory syndrome. 49 The genes for mutations in the MEFV gene, thus raising the probability of coinheriting other contributory mutations under DI.…”

The cardiac niche role in cardiomyocyte differentiation of rat bone marrow-derived stromal cells: comparison between static and microfluidic cell culture methods

“…This transcription factor, as well as Nkx2.5, are key players in early heart development by affecting the expression of several encoding cardiac-specific protein genes (Farlie et al, 2017[7]; Yang et al, 2009[32]). Moreover, the cTnT and cTnI are expressed in adult murine hearts, and they regulate muscle contraction in response to intracellular calcium fluctuations (Petropoulou et al, 2017[20]). The CX43 is a type of gap junction proteins that connect neighboring cardiomyocytes; hence, this protein is vital for efficient electrical signals transduction to regulate coordinated contraction of the cardiomyocytes for blood pumping (Yang et al, 2009[32]).…”

“…The CX43 is a type of gap junction proteins that connect neighboring cardiomyocytes; hence, this protein is vital for efficient electrical signals transduction to regulate coordinated contraction of the cardiomyocytes for blood pumping (Yang et al, 2009[32]). β-MHC is the main cardiac thick filament protein that partakes to cardiac muscle contraction (Petropoulou et al, 2017[20]). Although the increased expression of Nkx2.5, GATA4, and CX43 early in week 2 can be a sign of differentiation into cardiac progenitor cells, however, the expression of cTnT, cTnI, CX43, and β-MHC on week 4 can lead us to conclude that BMSCs have differentiated into more mature cardiomyocytes-like with the passage of time.…”

iTRAQ‑based quantitative proteomics analysis of the potential application of secretoneurin gene therapy for cardiac hypertrophy induced by DL‑isoproterenol hydrochloride in mice

“…These three proteins were Hadhb, Apoc3 and Myh7. Myh7 is a slow molecular ATPase involved in muscle contraction (49) and several studies have demonstrated that the gene encoding for this protein is mutated in cardiac hypertrophy, resulting in altered protein expression levels (50)(51)(52). Hadhb is involved in the pathway of fatty acid β-oxidation.…”