title: Coexistence of Digenic Mutations in Both Thin (TPM1) and Thick (MYH7) Filaments of Sarcomeric Genes Leads to Severe Hypertrophic Cardiomyopathy in a South Indian FHCM.
abstract: Mutations in sarcomeric genes are the leading cause for cardiomyopathies. However, not many genetic studies have been carried out on Indian cardiomyopathy patients. We performed sequence analyses of a thin filament sarcomeric gene, α-tropomyosin (TPM1), in 101 hypertrophic cardiomyopathy (HCM) patients and 147 dilated cardiomyopathy (DCM) patients against 207 ethnically matched healthy controls, revealing 13 single nucleotide polymorphisms (SNPs). Of these, one mutant, S215L, was identified in two unrelated HCM cases-patient #1, aged 44, and patient #2, aged 65-and was cosegregating with disease in these families as an autosomal dominant trait. In contrast, S215L was completely absent in 147 DCM and 207 controls. Patient #1 showed a more severe disease phenotype, with poor prognosis and a family history of sudden cardiac death, than patient #2. Therefore, these two patients and the family members positive for S215L were further screened for variations in MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, and ACTC. Interestingly, two novel thick filaments, D896N (homozygous) and I524K (heterozygous) mutations, in the MYH7 gene were identified exclusively in patient #1 and his family members. Thus, we strongly suggest that the coexistence of these digenic mutations is rare, but leads to severe hypertrophy in a South Indian familial hypertrophic cardiomyopathy (FHCM).
authors.affiliation: 1 CSIR-Centre for Cellular and Molecular Biology (CCMB) , Hyderabad, Telangana, India .
authors.forename: Deepa
authors.initials: D
authors.lastname: Selvi Rani
authors.forename: Pratibha
authors.initials: P
authors.lastname: Nallari
authors.forename: Perundurai S
authors.initials: PS
authors.lastname: Dhandapany
authors.forename: Jhansi
authors.initials: J
authors.lastname: Rani
authors.forename: Khunza
authors.initials: K
authors.lastname: Meraj
authors.forename: Mala
authors.initials: M
authors.lastname: Ganesan
authors.forename: Calambur
authors.initials: C
authors.lastname: Narasimhan
authors.forename: Kumarasamy
authors.initials: K
authors.lastname: Thangaraj
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D024722:Cardiac Myosins / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003599:Cytoskeleton; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D018995:Myosin Heavy Chains / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011379:Prognosis; D012518:Sarcomeres / Q000235:genetics; D014335:Tropomyosin / Q000235:genetics*; D055815:Young Adult
chemical_list: C501641:MYH7 protein, human; C490775:TPM1 protein, human; D014335:Tropomyosin; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains