Genotype-Phenotype Associations with Restrictive Cardiomyopathy Induced by Pathogenic Genetic Mutations

Abstract

Restrictive cardiomyopathy (RCM) is an uncommon cardiac muscle disease characterized by impaired ventricular filling and severe diastolic dysfunction with or without systolic dysfunction. The patients with RCM present poor prognosis and high prevalence of sudden cardiac death, especially in the young. The etiology of RCM may be idiopathic, familial or acquired predispositions from various systemic diseases. The genetic background of familial RCM is often caused by mutations in genes encoding proteins of sarcomeres and a significant minority by mutations in non-sarcomeric proteins and transthyretin proteins. It is important to identify the associations between genotype and phenotype to guide clinical diagnosis and treatment. Here, we have summarized the reported index cases with RCM involving genetic etiology to date and highlighted the most significant phenotype results.

Exploring TTN variants as genetic insights into cardiomyopathy pathogenesis and potential emerging clues to molecular mechanisms in cardiomyopathies

“…Numerous genes that encode non-sarcomeric, sarcomeric, and sarcomere-associated proteins have been shown to play a role in RCM occurrence and inheritance. Examples include the TTR gene variants (V122I; I68L; L111M; T60A; S23N; P24S; W41L; V30M; V20I) and APOA1 gene in Amyloidosis; GLA gene in Fabry disease; GBA gene in Gaucher disease; HAMP , HFE , HFE2 , HJV , PNPLA3 , SLC40A1 , TfR2 genes in Hereditary hemochromatosis; NPC1 , NPC2 and SMPD1 genes in Niemann-Pick disease; AG3, CRYAB, DES, DNAJB6, FHL1, FLNC, LDB3, and MYOT genes in Myofibrillar myopathies; ABCC6 gene in Pseudoxanthoma elasticum; ACTC, MHC, TNNT2, TNNI3, TNNC1, DES, MYH, MYL3 , and CRYAB genes in Sarcomeric protein disorders; WRN gene in Werner's syndrome; and BMP5 , BMP7 and TAZ genes in Endocardial fibroelastosis 1 , 2 , 106 , 107 .…”

“…HCM is speculated to arise from mutations in sarcomere-related genes; nonetheless, the exact pathophysiology of HCM is yet to be found 90 . Mutations in Sarcomeric, non-sarcomeric, and sarcomere-associated proteins are proposed to contribute to the development and inheritance of RCM 1 , 2 , 106 , 107 . Although the role of TTN variants in the pathogenesis and inheritance of RCM is not fully understood, it is known that titin is the key determinant of sarcomere resting tension and diastolic function 36 , 108 , 109 .…”