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Cesar Moris - One of the best experts on this subject based on the ideXlab platform.
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espectro mutacional de los genes sarcomericos myh7 mybpc3 tnnt2 TNNI3 y tpm1 en pacientes con miocardiopatia hipertrofica
Revista Espanola De Cardiologia, 2009Co-Authors: Monica Garciacastro, Eliecer Coto, Julian R Reguero, J R Berrazueta, Victoria Alvarez, Belen Alonso, Rocio Sainz, Maria Martin, Cesar MorisAbstract:Introduccion y objetivos. Las mutaciones en los genes sarcomericos son la causa mas frecuente de miocardiopatia hipertrofica. Para cada gen, la frecuencia de mutaciones varia entre los estudios, y las manifestaciones clinicas son muy heterogeneas, lo que dificulta el empleo de la informacion genetica en la practica clinica. Nuestro objetivo es determinar la frecuencia de mutaciones en los genes sarcomericos MYH7, MYBPC3, TNNT2, TNNI3 y TPM1 en una serie de pacientes con miocardiopatia hipertrofica. Metodos. Se analizaron las regiones codificantes de estos cinco genes mediante secuenciacion en 120 pacientes (el 29% con antecedentes familiares), comparando el fenotipo segun el gen mutado. Resultados. Se hallaron mutaciones en 32 pacientes; 10 y 20 tenian mutaciones en MYH7 (8%) y MYBPC3 (16%). Se hallaron mutaciones de TNNT2 y TPM1 en 2 y 1 pacientes, y ninguna de TNNI3. Dos pacientes tenian dos mutaciones (dobles mutantes). El 61% de las mutaciones no habian sido descritas previamente. No hallamos diferencias en la media de edad al diagnostico o el tamano de la hipertrofia entre los portadores de mutaciones en MYH7 y los de MYBPC3. Conclusiones. El 26% de los pacientes tenian mutaciones en alguno de los cinco genes estudiados. Mas de la mitad de las mutaciones no habian sido descritas. El gen MYBPC3 fue el mas mutado, seguido de MYH7. No se hallaron diferencias fenotipicas entre los pacientes segun el gen mutado, lo que dificultaria el empleo de la informacion genetica para estratificar el riesgo en estos pacientes.
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Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy
Revista espanola de cardiologia, 2009Co-Authors: Mónica García-castro, Eliecer Coto, Julian R Reguero, J R Berrazueta, Victoria Alvarez, Belen Alonso, Rocio Sainz, Maria Martin, Cesar MorisAbstract:Introduction and objectives Mutation of a sarcomeric gene is the most frequent cause of hypertrophic cardiomyopathy. For each such gene, however, previous studies have reported a range of different mutation frequencies, and clinical manifestations have been highly heterogeneous, both of which limit the use of genetic information in clinical practice. Our aim was to determine the frequency of mutations in the sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3 , and TPM1 in a cohort of Spanish patients with hypertrophic cardiomyopathy. Methods We used sequencing to analyze the coding regions of these five genes in 120 patients (29% with a family history) and investigated how the patient phenotype varied with the gene mutated. Results In total, 32 patients were found to have mutations: 10 in MYH7 (8%), 20 in MYBPC3 (16%), 2 in TNNT2 , 1 in TPM1 , and none in TNNI3 . Overall, 61% of mutations had not been described before. Two patients had 2 mutations (ie, double mutants). There was no difference in the mean age at diagnosis or the extent of the hypertrophy between those with MYH7 mutations and those with MYBPC3 mutations. Conclusions Some 26% of patients had a mutation in one of the five sarcomeric genes investigated. More than half of the mutations had not been described before. The MYBPC3 gene was the most frequently mutated, followed by MYH7 . No phenotypic differences were observed between carriers of the various mutations, which makes it difficult to use genetic information to stratify risk in these patients.
Kumarasamy Thangaraj - One of the best experts on this subject based on the ideXlab platform.
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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
DNA and cell biology, 2015Co-Authors: Deepa Selvi Rani, Pratibha Nallari, Jhansi Rani, Calambur Narasimhan, Perundurai S. Dhandapany, Khunza Meraj, Mala Ganesan, Kumarasamy ThangarajAbstract: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. I...
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high prevalence of arginine to glutamine substitution at 98 141 and 162 positions in troponin i TNNI3 associated with hypertrophic cardiomyopathy among indians
BMC Medical Genetics, 2012Co-Authors: Deepa Selvi Rani, Pratibha Nallari, Calambur Narasimhan, Singh Priyamvada, Lalji Singh, Kumarasamy ThangarajAbstract:Troponin I (TNNI3) is the inhibitory subunit of the thin filament regulatory complex Troponin, which confers calcium-sensitivity to striated muscle actomyosin ATPase activity. Mutations (2-7%) in this gene had been reported in hypertrophic cardiomyopathy patients (HCM). However, the frequencies of mutations and associated clinical presentation have not been established in cardiomyopathy patients of Indian origin, hence we have undertaken this study. We have sequenced all the exons, including the exon-intron boundaries of TNNI3 gene in 101 hypertrophic cardiomyopathy patients (HCM), along with 160 healthy controls, inhabited in the same geographical region of southern India. Our study revealed a total of 16 mutations. Interestingly, we have observed Arginine to Glutamine (R to Q) mutation at 3 positions 98, 141 and 162, exclusively in HCM patients with family history of sudden cardiac death. The novel R98Q was observed in a severe hypertrophic obstructive cardiomyopathy patient (HOCM). The R141Q mutation was observed in two familial cases of severe asymmetric septal hypertrophy (ASH++). The R162Q mutation was observed in a ASH++ patient with mean septal thickness of 29 mm, and have also consists of allelic heterogeneity by means of having one more synonymous (E179E) mutation at g.4797: G → A: in the same exon 7, which replaces a very frequent codon (GAG: 85%) with a rare codon (GAA: 14%). Screening for R162Q mutation in all the available family members revealed its presence in 9 individuals, including 7 with allelic heterogeneity (R162Q and E179E) of which 4 were severely affected. We also found 2 novel SNPs, (g.2653; G → A and g.4003 C → T) exclusively in HCM, and in silico analysis of these SNPs have predicted to cause defect in recognition/binding sites for proteins responsible for proper splicing. Our study has provided valuable information regarding the prevalence of TNNI3 mutations in Indian HCM patients and its risk assessment, these will help in genetic counseling and to adopt appropriate treatment strategies.
Deepa Selvi Rani - One of the best experts on this subject based on the ideXlab platform.
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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
DNA and cell biology, 2015Co-Authors: Deepa Selvi Rani, Pratibha Nallari, Jhansi Rani, Calambur Narasimhan, Perundurai S. Dhandapany, Khunza Meraj, Mala Ganesan, Kumarasamy ThangarajAbstract: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. I...
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high prevalence of arginine to glutamine substitution at 98 141 and 162 positions in troponin i TNNI3 associated with hypertrophic cardiomyopathy among indians
BMC Medical Genetics, 2012Co-Authors: Deepa Selvi Rani, Pratibha Nallari, Calambur Narasimhan, Singh Priyamvada, Lalji Singh, Kumarasamy ThangarajAbstract:Troponin I (TNNI3) is the inhibitory subunit of the thin filament regulatory complex Troponin, which confers calcium-sensitivity to striated muscle actomyosin ATPase activity. Mutations (2-7%) in this gene had been reported in hypertrophic cardiomyopathy patients (HCM). However, the frequencies of mutations and associated clinical presentation have not been established in cardiomyopathy patients of Indian origin, hence we have undertaken this study. We have sequenced all the exons, including the exon-intron boundaries of TNNI3 gene in 101 hypertrophic cardiomyopathy patients (HCM), along with 160 healthy controls, inhabited in the same geographical region of southern India. Our study revealed a total of 16 mutations. Interestingly, we have observed Arginine to Glutamine (R to Q) mutation at 3 positions 98, 141 and 162, exclusively in HCM patients with family history of sudden cardiac death. The novel R98Q was observed in a severe hypertrophic obstructive cardiomyopathy patient (HOCM). The R141Q mutation was observed in two familial cases of severe asymmetric septal hypertrophy (ASH++). The R162Q mutation was observed in a ASH++ patient with mean septal thickness of 29 mm, and have also consists of allelic heterogeneity by means of having one more synonymous (E179E) mutation at g.4797: G → A: in the same exon 7, which replaces a very frequent codon (GAG: 85%) with a rare codon (GAA: 14%). Screening for R162Q mutation in all the available family members revealed its presence in 9 individuals, including 7 with allelic heterogeneity (R162Q and E179E) of which 4 were severely affected. We also found 2 novel SNPs, (g.2653; G → A and g.4003 C → T) exclusively in HCM, and in silico analysis of these SNPs have predicted to cause defect in recognition/binding sites for proteins responsible for proper splicing. Our study has provided valuable information regarding the prevalence of TNNI3 mutations in Indian HCM patients and its risk assessment, these will help in genetic counseling and to adopt appropriate treatment strategies.
Matthew B Dobbs - One of the best experts on this subject based on the ideXlab platform.
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variants in genes that encode muscle contractile proteins influence risk for isolated clubfoot
American Journal of Medical Genetics Part A, 2011Co-Authors: Katelyn S Weymouth, Susan H Blanton, Michael J Bamshad, Anita E Beck, Christine M Alvarez, Steve Richards, Christina A Gurnett, Matthew B DobbsAbstract:Isolated clubfoot is a relatively common birth defect that affects approximately 4,000 newborns in the US each year. Calf muscles in the affected leg(s) are underdeveloped and remain small even after corrective treatment. This observation suggests that variants in genes that influence muscle development are priority candidate risk factors for clubfoot. This contention is further supported by the discovery that mutations in genes that encode components of the muscle contractile complex (MYH3, TPM2, TNNT3, TNNI2, and MYH8) cause congenital contractures, including clubfoot, in distal arthrogryposis (DA) syndromes. Interrogation of fifteen genes encoding proteins that control myofiber contractility in a cohort of both nonHispanic white (NHW) and Hispanic families, identified positive associations (p<0.05) with SNPs in twelve genes; only one was identified in a family-based validation dataset. Six SNPs in TNNC2 deviated from Hardy Weinberg Equilibrium (HWE) in mothers in our NHW discovery dataset. Relative risk and likelihood ratio tests showed evidence for a maternal genotypic effect with TNNC2/rs383112 and an inherited/child genotypic effect with two SNPs, TNNC2/rs4629 and rs383112. Associations with multiple SNPs in TPM1 were identified in the NHW discovery (rs4075583, p=0.01), family-based validation (rs1972041, p=0.000074) and case-control validation (rs12148828, p=0.04) datasets. Gene interactions were identified between multiple muscle contraction genes with many of the interactions involving at least one potential regulatory SNP. Collectively, our results suggest that variation in genes that encode contractile proteins of skeletal myofibers may play a role in the etiology of clubfoot.
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skeletal muscle contractile gene tnnt3 myh3 tpm2 mutations not found in vertical talus or clubfoot
Clinical Orthopaedics and Related Research, 2009Co-Authors: Christina A Gurnett, Matthew B Dobbs, Farhang Alaee, David M Desruisseau, Stephanie BoehmAbstract:Arthrogryposis presents with lower limb contractures that resemble clubfoot and/or vertical talus. Recently, mutations in skeletal muscle contractile genes MYH3 (myosin heavy chain 3), TNNT3 (troponin T3), and TPM2 (tropomyosin 2) were identified in patients with distal arthrogryposis DA2A (Freeman-Sheldon syndrome) or DA2B (Sheldon-Hall syndrome). We asked whether the contractile genes responsible for distal arthrogryposis are also responsible for cases of familial clubfoot or vertical talus. We determined the frequency of MYH3, TNNT3, and TPM2 mutations in patients with idiopathic clubfoot, vertical talus, and distal arthrogryposis type 1 (DA1). We resequenced the coding exons of the MYH3, TNNT3, and TPM2 genes in 31 patients (five with familial vertical talus, 20 with familial clubfoot, and six with DA1). Variants were evaluated for segregation with disease in additional family members, and the frequency of identified variants was determined in a control population. In one individual with DA1, we identified a de novo TNNT3 mutation (R63H) previously identified in an individual with DA2B. No other causative mutations were identified, though we found several previously undescribed single-nucleotide polymorphisms of unknown importance. Although mutations in MYH3, TNNT3, and TPM2 are frequently associated with distal arthrogryposis syndromes, they were not present in patients with familial vertical talus or clubfoot. The TNNT3 R63H recurrent mutation identified in two unrelated individuals may be associated with either DA1 or DA2B.
Eugen Sandica - One of the best experts on this subject based on the ideXlab platform.
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High proportion of genetic cases in patients with advanced cardiomyopathy including a novel homozygous Plakophilin 2-gene mutation
PloS one, 2017Co-Authors: Baerbel Klauke, Anna Gaertner-rommel, Uwe Schulz, Astrid Kassner, Edzard Zu Knyphausen, Thorsten Laser, Deniz Kececioglu, Lech Paluszkiewicz, Ute Blanz, Eugen SandicaAbstract:Cardiomyopathies might lead to end-stage heart disease with the requirement of drastic treatments like bridging up to transplant or heart transplantation. A not precisely known proportion of these diseases are genetically determined. We genotyped 43 index-patients (30 DCM, 10 ARVC, 3 RCM) with advanced or end stage cardiomyopathy using a gene panel which covered 46 known cardiomyopathy disease genes. Fifty-three variants with possible impact on disease in 33 patients were identified. Of these 27 (51%) were classified as likely pathogenic or pathogenic in the MYH7, MYL2, MYL3, NEXN, TNNC1, TNNI3, DES, LMNA, PKP2, PLN, RBM20, TTN, and CRYAB genes. Fifty-six percent (n = 24) of index-patients carried a likely pathogenic or pathogenic mutation. Of these 75% (n = 18) were familial and 25% (n = 6) sporadic cases. However, severe cardiomyopathy seemed to be not characterized by a specific mutation profile. Remarkably, we identified a novel homozygous PKP2-missense variant in a large consanguineous family with sudden death in early childhood and several members with heart transplantation in adolescent age.
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Variant carrying genes.
2017Co-Authors: Baerbel Klauke, Anna Gaertner-rommel, Uwe Schulz, Astrid Kassner, Edzard Zu Knyphausen, Thorsten Laser, Deniz Kececioglu, Lech Paluszkiewicz, Ute Blanz, Eugen SandicaAbstract:In DCM-cases TTN carried the most variants. Of 19 TTN-variants in DCM-cases, 6 were truncating variants. The other affected genes were TNNT2, TNNC1, RBM20, PKP2, NEXN, MYL2, MYH7, LMNA, DSP, and DES. In ARVC-cases predominantly PKP2- and TTN-variants were identified. Further variants were found in the genes PRKAG2, PLN, MYH7, MYH6, LMNA, and DES. In the cohort of the RCM-cases variants in 3 different genes were identified: TNNI3, MYL3, and CRYAB. ACMG class 3–5 = variant of uncertain significance, likely pathogenic, pathogenic, respectively.