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Luisa Mestroni - One of the best experts on this subject based on the ideXlab platform.
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tafazzin gene mutations are uncommon causes of Dilated Cardiomyopathy in adults
Cardiogenetics, 2011Co-Authors: Matthew R G Taylor, Deborah Ferguson, Jean Jirikowic, Andrea Di Lenarda, Gianfranco Sinagra, Ernesto E. Salcedo, Dobromir Slavov, Luisa MestroniAbstract:Barth syndrome is an X-linked genetic condition featuring neutropenia, skeletal myopathy, and Dilated Cardiomyopathy in boys due to tafazzin (TAZ) mutations. Pure Dilated Cardiomyopathy without other features of Barth syndrome may also result from TAZ mutations and survival into adulthood has been described. Although TAZ testing is routinely included in Dilated Cardiomyopathy panels in adults, the prevalence of TAZ mutations in the adult population, including women who may be at risk to develop later onset disease due to TAZ mutations, has not been measured. We screened 292 families with Dilated Cardiomyopathy (209 male and 83 female probands) for TAZ mutations using denaturing high-performance liquid chromatography and sequence analysis. Putative mutations were evaluated based on standard criteria including screening available relatives and healthy controls and for effects on splicing efficiency in the case of one intronic variant. Two variants suspicious for being pathogenic were found in two unrelated families (c.387T>C, Phe128Ser and c.507C>T, Leu169Leu). The Phe128Ser variant had been previously reported as a pathogenic mutation; however we determined that this variant is instead a rare polymorphism restricted to African Americans. The Leu169Leu variant was detected in a male patient and altered RNA processing in our minigene assay supporting a pathogenic role. No mutations in female subjects were detected. Tafazzin mutations were rare in our population of adults with Dilated Cardiomyopathy and none were found in females. Our findings indicate that genetic testing for tafazzin should not be routinely performed in Dilated Cardiomyopathy as suggested by current guidelines. Furthermore, the Phe128Ser variant is not pathogenic, but likely represents a benign polymorphism in persons of African American ancestry.
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scn5a mutations associate with arrhythmic Dilated Cardiomyopathy and commonly localize to the voltage sensing mechanism
Journal of the American College of Cardiology, 2011Co-Authors: William P Mcnair, Matthew R G Taylor, Andrea Di Lenarda, Gianfranco Sinagra, Ernesto E. Salcedo, Dobromir Slavov, Debra A Ferguson, Xiao Zhu, John H Caldwell, Luisa MestroniAbstract:Objectives: The aim of this study was to discern the role of the cardiac voltage-gated sodium ion channel SCN5A in the etiology of Dilated Cardiomyopathy (DCM).Background: Dilated Cardiomyopathy as...
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familial Dilated Cardiomyopathy evidence for genetic and phenotypic heterogeneity
Journal of the American College of Cardiology, 1999Co-Authors: Luisa Mestroni, Andrea Di Lenarda, Gianfranco Sinagra, Matteo Vatta, B Pinamonti, F Muntoni, Chiara Rocco, Dario Gregori, Snjezana Miocic, Alida L P CaforioAbstract:Abstract OBJECTIVES This study was performed to evaluate the characteristics, mode of inheritance and etiology of familial Dilated Cardiomyopathy (FDC). BACKGROUND A genetic form of disease transmission has been identified in a relevant proportion of patients with Dilated Cardiomyopathy (DCM). Variable clinical characteristics and patterns of inheritance, and an increased frequency of cardiac antibodies have been reported. An analysis of FDC may improve the understanding of the disease and the management of patients. METHODS Of 350 consecutive patients with idiopathic DCM, 281 relatives from 60 families were examined. Family studies included clinical examination, electrocardiography, echocardiography and blood sampling. Of the 60 DCM index patients examined, 39 were attributable to FDC and 21 were due to sporadic DCM. Clinical features, histology, mode of inheritance and autoimmune serology were examined, molecular genetic studies were undertaken and the difference between familial and sporadic forms was analyzed. RESULTS Only a younger age (p = 0.0005) and a higher ejection fraction (p = 0.03) could clinically distinguish FDC patients from those with sporadic DCM. However, a number of distinct subtypes of FDC were identified: 1) autosomal dominant, the most frequent form (56%); 2) autosomal recessive (16%), characterized by worse prognosis; 3) X-linked FDC (10%), with different mutations of the dystrophin gene; 4) a novel form of autosomal dominant DCM with subclinical skeletal muscle disease (7.7%); 5) FDC with conduction defects (2.6%), and 6) rare unclassifiable forms (7.7%). The forms with skeletal muscle involvement were characterized by a restrictive filling pattern; the forms with isolated Cardiomyopathy had an increased frequency of organ-specific cardiac autoantibodies. Histologic signs of myocarditis were frequent and nonspecific. CONCLUSIONS Familial Dilated Cardiomyopathy is frequent, cannot be predicted on a clinical or morphologic basis and requires family screening for identification. The phenotypic heterogeneity, different patterns of transmission, different frequencies of cardiac autoantibodies and the initial molecular genetic data indicate that multiple genes and pathogenetic mechanisms can lead to FDC.
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linkage of familial Dilated Cardiomyopathy to chromosome 9
American Journal of Human Genetics, 1995Co-Authors: Maja Krajinovic, Gianfranco Sinagra, Matteo Vatta, B Pinamonti, Giovanni Maria Severini, Jelena Milasin, Arturo Falaschi, F Camerini, Mauro Giacca, Luisa MestroniAbstract:Idiopathic Dilated Cardiomyopathy is a heart muscle disease of unknown etiology, characterized by impaired myocardial contractility and ventricular dilatation. The disorder is an important cause of morbidity and mortality and represents the chief indication for heart transplantation. Familial transmission is often recognized (familial Dilated Cardiomyopathy, or FDC), mostly with autosomal dominant inheritance. In order to understand the molecular genetic basis of the disease, a large six-generation kindred with autosomal dominant FDC was studied for linkage analysis. A genome-wide search was undertaken after a large series of candidate genes were excluded and was then extended to two other families with autosomal dominant pattern of transmission and identical clinical features. Coinheritance of the disease gene was excluded for >95% of the genome, after 251 polymorphic markers were analyzed. Linkage was found for chromosome 9q13-q22, with a maximum multipoint lod score of 4.2. There was no evidence of heterogeneity. The FDC locus was placed in the interval between loci D9S153 and D9S152. Several candidate genes for causing Dilated Cardiomyopathy map in this region. 33 refs., 3 figs., 1 tab.
Gianfranco Sinagra - One of the best experts on this subject based on the ideXlab platform.
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evolving concepts in Dilated Cardiomyopathy
European Journal of Heart Failure, 2018Co-Authors: Marco Merlo, Antonio Cannata, Marco Gobbo, Davide Stolfo, Perry M Elliott, Gianfranco SinagraAbstract:Dilated Cardiomyopathy (DCM) represents a particular aetiology of systolic heart failure that frequently has a genetic background and usually affects young patients with few co-morbidities. The prognosis of DCM has improved substantially during the last decades due to more accurate aetiological characterization, the red-flag integrated approach to the disease, early diagnosis through systematic familial screening, and the concept of DCM as a dynamic disease requiring constant optimization of medical and non-pharmacological evidence-based treatments. However, some important issues in clinical management remain unresolved, including the role of cardiac magnetic resonance for diagnosis and risk categorization and the interaction between genotype and clinical phenotype, and arrhythmic risk stratification. This review offers a comprehensive survey of these and other emerging issues in the clinical management of DCM, providing where possible practical recommendations.
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tafazzin gene mutations are uncommon causes of Dilated Cardiomyopathy in adults
Cardiogenetics, 2011Co-Authors: Matthew R G Taylor, Deborah Ferguson, Jean Jirikowic, Andrea Di Lenarda, Gianfranco Sinagra, Ernesto E. Salcedo, Dobromir Slavov, Luisa MestroniAbstract:Barth syndrome is an X-linked genetic condition featuring neutropenia, skeletal myopathy, and Dilated Cardiomyopathy in boys due to tafazzin (TAZ) mutations. Pure Dilated Cardiomyopathy without other features of Barth syndrome may also result from TAZ mutations and survival into adulthood has been described. Although TAZ testing is routinely included in Dilated Cardiomyopathy panels in adults, the prevalence of TAZ mutations in the adult population, including women who may be at risk to develop later onset disease due to TAZ mutations, has not been measured. We screened 292 families with Dilated Cardiomyopathy (209 male and 83 female probands) for TAZ mutations using denaturing high-performance liquid chromatography and sequence analysis. Putative mutations were evaluated based on standard criteria including screening available relatives and healthy controls and for effects on splicing efficiency in the case of one intronic variant. Two variants suspicious for being pathogenic were found in two unrelated families (c.387T>C, Phe128Ser and c.507C>T, Leu169Leu). The Phe128Ser variant had been previously reported as a pathogenic mutation; however we determined that this variant is instead a rare polymorphism restricted to African Americans. The Leu169Leu variant was detected in a male patient and altered RNA processing in our minigene assay supporting a pathogenic role. No mutations in female subjects were detected. Tafazzin mutations were rare in our population of adults with Dilated Cardiomyopathy and none were found in females. Our findings indicate that genetic testing for tafazzin should not be routinely performed in Dilated Cardiomyopathy as suggested by current guidelines. Furthermore, the Phe128Ser variant is not pathogenic, but likely represents a benign polymorphism in persons of African American ancestry.
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scn5a mutations associate with arrhythmic Dilated Cardiomyopathy and commonly localize to the voltage sensing mechanism
Journal of the American College of Cardiology, 2011Co-Authors: William P Mcnair, Matthew R G Taylor, Andrea Di Lenarda, Gianfranco Sinagra, Ernesto E. Salcedo, Dobromir Slavov, Debra A Ferguson, Xiao Zhu, John H Caldwell, Luisa MestroniAbstract:Objectives: The aim of this study was to discern the role of the cardiac voltage-gated sodium ion channel SCN5A in the etiology of Dilated Cardiomyopathy (DCM).Background: Dilated Cardiomyopathy as...
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prevalence of desmin mutations in Dilated Cardiomyopathy
Circulation, 2007Co-Authors: Matthew R G Taylor, Andrea Di Lenarda, Gianfranco Sinagra, Dobromir Slavov, Debra A Ferguson, Elisa Carniel, Kurt W Haubold, Mark M Boucek, Sharon L Graw, Xiao ZhuAbstract:Background— Desmin-related myofibrillar myopathy (DRM) is a cardiac and skeletal muscle disease caused by mutations in the desmin (DES) gene. Mutations in the central 2B domain of DES cause skeletal muscle disease that typically precedes cardiac involvement. However, the prevalence of DES mutations in Dilated Cardiomyopathy (DCM) without skeletal muscle disease is not known. Methods and Results— Denaturing high-performance liquid chromatography was used to screen DES for mutations in 116 DCM families from the Familial Dilated Cardiomyopathy Registry and in 309 subjects with DCM from the Beta-Blocker Evaluation of Survival Trial (BEST). DES mutations were transfected into SW13 and human smooth muscle cells and neonatal rat cardiac myocytes, and the effects on cytoskeletal desmin network architecture were analyzed with confocal microscopy. Five novel missense DES mutations, including the first localized to the highly conserved 1A domain, were detected in 6 subjects (1.4%). Transfection of DES mutations in t...
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familial Dilated Cardiomyopathy evidence for genetic and phenotypic heterogeneity
Journal of the American College of Cardiology, 1999Co-Authors: Luisa Mestroni, Andrea Di Lenarda, Gianfranco Sinagra, Matteo Vatta, B Pinamonti, F Muntoni, Chiara Rocco, Dario Gregori, Snjezana Miocic, Alida L P CaforioAbstract:Abstract OBJECTIVES This study was performed to evaluate the characteristics, mode of inheritance and etiology of familial Dilated Cardiomyopathy (FDC). BACKGROUND A genetic form of disease transmission has been identified in a relevant proportion of patients with Dilated Cardiomyopathy (DCM). Variable clinical characteristics and patterns of inheritance, and an increased frequency of cardiac antibodies have been reported. An analysis of FDC may improve the understanding of the disease and the management of patients. METHODS Of 350 consecutive patients with idiopathic DCM, 281 relatives from 60 families were examined. Family studies included clinical examination, electrocardiography, echocardiography and blood sampling. Of the 60 DCM index patients examined, 39 were attributable to FDC and 21 were due to sporadic DCM. Clinical features, histology, mode of inheritance and autoimmune serology were examined, molecular genetic studies were undertaken and the difference between familial and sporadic forms was analyzed. RESULTS Only a younger age (p = 0.0005) and a higher ejection fraction (p = 0.03) could clinically distinguish FDC patients from those with sporadic DCM. However, a number of distinct subtypes of FDC were identified: 1) autosomal dominant, the most frequent form (56%); 2) autosomal recessive (16%), characterized by worse prognosis; 3) X-linked FDC (10%), with different mutations of the dystrophin gene; 4) a novel form of autosomal dominant DCM with subclinical skeletal muscle disease (7.7%); 5) FDC with conduction defects (2.6%), and 6) rare unclassifiable forms (7.7%). The forms with skeletal muscle involvement were characterized by a restrictive filling pattern; the forms with isolated Cardiomyopathy had an increased frequency of organ-specific cardiac autoantibodies. Histologic signs of myocarditis were frequent and nonspecific. CONCLUSIONS Familial Dilated Cardiomyopathy is frequent, cannot be predicted on a clinical or morphologic basis and requires family screening for identification. The phenotypic heterogeneity, different patterns of transmission, different frequencies of cardiac autoantibodies and the initial molecular genetic data indicate that multiple genes and pathogenetic mechanisms can lead to FDC.
Ramon Brugada - One of the best experts on this subject based on the ideXlab platform.
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familial Dilated Cardiomyopathy caused by a novel frameshift in the bag3 gene
PLOS ONE, 2016Co-Authors: Rocio Toro, Alexandra Perezserra, Oscar Campuzano, Javier Moncayoarlandi, Catarina Allegue, Anna Iglesias, A Mangas, Ramon BrugadaAbstract:Background Dilated Cardiomyopathy, a major cause of chronic heart failure and cardiac transplantation, is characterized by left ventricular or biventricular heart dilatation. In nearly 50% of cases the pathology is inherited, and more than 60 genes have been reported as disease-causing. However, in 30% of familial cases the mutation remains unidentified even after comprehensive genetic analysis. This study clinically and genetically assessed a large Spanish family affected by Dilated Cardiomyopathy to search for novel variations.
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familial Dilated Cardiomyopathy caused by a novel frameshift in the bag3 gene
PLOS ONE, 2016Co-Authors: Rocio Toro, Alexandra Perezserra, Oscar Campuzano, Javier Moncayoarlandi, Catarina Allegue, Anna Iglesias, A Mangas, Ramon BrugadaAbstract:Background Dilated Cardiomyopathy, a major cause of chronic heart failure and cardiac transplantation, is characterized by left ventricular or biventricular heart dilatation. In nearly 50% of cases the pathology is inherited, and more than 60 genes have been reported as disease-causing. However, in 30% of familial cases the mutation remains unidentified even after comprehensive genetic analysis. This study clinically and genetically assessed a large Spanish family affected by Dilated Cardiomyopathy to search for novel variations. Methods and Results Our study included a total of 100 family members. Clinical assessment was performed in alive, and genetic analysis was also performed in alive and 1 deceased relative. Genetic screening included resequencing of 55 genes associated with sudden cardiac death, and Sanger sequencing of main disease-associated genes. Genetic analysis identified a frame-shift variation in BAG3 (p.H243Tfr*64) in 32 patients. Genotype-phenotype correlation identified substantial heterogeneity in disease expression. Of 32 genetic carriers (one deceased), 21 relatives were clinically affected, and 10 were asymptomatic. Seventeen of the symptomatic genetic carriers exhibited proto-diastolic septal knock by echocardiographic assessment. Conclusions We report p.H243Tfr*64_BAG3 as a novel pathogenic variation responsible for familial Dilated Cardiomyopathy. This variation correlates with a more severe phenotype of the disease, mainly in younger individuals. Genetic analysis in families, even asymptomatic individuals, enables early identification of individuals at risk and allows implementation of preventive measures.
Catrin S Rutland - One of the best experts on this subject based on the ideXlab platform.
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multiple genetic associations with irish wolfhound Dilated Cardiomyopathy
BioMed Research International, 2016Co-Authors: Siobhan Simpson, Malcolm Cobb, Nigel P Mongan, Mark Dunning, Serena Brownlie, Janika Patel, Megan Godden, Catrin S RutlandAbstract:Cardiac disease is a leading cause of morbidity and mortality in dogs and humans, with Dilated Cardiomyopathy being a large contributor to this. The Irish Wolfhound (IWH) is one of the most commonly affected breeds and one of the few breeds with genetic loci associated with the disease. Mutations in more than 50 genes are associated with human Dilated Cardiomyopathy (DCM), yet very few are also associated with canine DCM. Furthermore, none of the identified canine loci explain many cases of the disease and previous work has indicated that genotypes at multiple loci may act together to influence disease development. In this study, loci previously associated with DCM in IWH were tested for associations in a new cohort both individually and in combination. We have identified loci significantly associated with the disease individually, but no genotypes individually or in pairs conferred a significantly greater risk of developing DCM than the population risk. However combining three loci together did result in the identification of a genotype which conferred a greater risk of disease than the overall population risk. This study suggests multiple rather than individual genetic factors, cooperating to influence DCM risk in IWH.
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a predictive model for canine Dilated Cardiomyopathy a meta analysis of doberman pinscher data
PeerJ, 2015Co-Authors: Siobhan Simpson, Jennifer Edwards, Richard D Emes, Malcolm Cobb, Nigel P Mongan, Catrin S RutlandAbstract:Dilated Cardiomyopathy is a prevalent and often fatal disease in humans and dogs. Indeed Dilated Cardiomyopathy is the third most common form of cardiac disease in humans, reported to affect approximately 36 individuals per 100,000 individuals. In dogs, Dilated Cardiomyopathy is the second most common cardiac disease and is most prevalent in the Irish Wolfhound, Doberman Pinscher and Newfoundland breeds. Dilated Cardiomyopathy is characterised by ventricular chamber enlargement and systolic dysfunction which often leads to congestive heart failure. Although multiple human loci have been implicated in the pathogenesis of Dilated Cardiomyopathy, the identified variants are typically associated with rare monogenic forms of Dilated Cardiomyopathy. The potential for multigenic interactions contributing to human Dilated Cardiomyopathy remains poorly understood. Consistent with this, several known human Dilated Cardiomyopathy loci have been excluded as common causes of canine Dilated Cardiomyopathy, although canine Dilated Cardiomyopathy resembles the human disease functionally. This suggests additional genetic factors contribute to the Dilated Cardiomyopathy phenotype.This study represents a meta-analysis of available canine Dilated Cardiomyopathy genetic datasets with the goal of determining potential multigenic interactions relating the sex chromosome genotype (XX vs. XY) with known Dilated Cardiomyopathy associated loci on chromosome 5 and the PDK4 gene in the incidence and progression of Dilated Cardiomyopathy. The results show an interaction between known canine Dilated Cardiomyopathy loci and an unknown X-linked locus. Our study is the first to test a multigenic contribution to Dilated Cardiomyopathy and suggest a genetic basis for the known sex-disparity in Dilated Cardiomyopathy outcomes.
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A predictive model for canine Dilated Cardiomyopathy—a meta-analysis of Doberman Pinscher data
PeerJ Inc., 2015Co-Authors: Siobhan Simpson, Jennifer Edwards, Richard D Emes, Nigel P Mongan, Malcolm A. Cobb, Catrin S RutlandAbstract:Dilated Cardiomyopathy is a prevalent and often fatal disease in humans and dogs. Indeed Dilated Cardiomyopathy is the third most common form of cardiac disease in humans, reported to affect approximately 36 individuals per 100,000 individuals. In dogs, Dilated Cardiomyopathy is the second most common cardiac disease and is most prevalent in the Irish Wolfhound, Doberman Pinscher and Newfoundland breeds. Dilated Cardiomyopathy is characterised by ventricular chamber enlargement and systolic dysfunction which often leads to congestive heart failure. Although multiple human loci have been implicated in the pathogenesis of Dilated Cardiomyopathy, the identified variants are typically associated with rare monogenic forms of Dilated Cardiomyopathy. The potential for multigenic interactions contributing to human Dilated Cardiomyopathy remains poorly understood. Consistent with this, several known human Dilated Cardiomyopathy loci have been excluded as common causes of canine Dilated Cardiomyopathy, although canine Dilated Cardiomyopathy resembles the human disease functionally. This suggests additional genetic factors contribute to the Dilated Cardiomyopathy phenotype.This study represents a meta-analysis of available canine Dilated Cardiomyopathy genetic datasets with the goal of determining potential multigenic interactions relating the sex chromosome genotype (XX vs. XY) with known Dilated Cardiomyopathy associated loci on chromosome 5 and the PDK4 gene in the incidence and progression of Dilated Cardiomyopathy. The results show an interaction between known canine Dilated Cardiomyopathy loci and an unknown X-linked locus. Our study is the first to test a multigenic contribution to Dilated Cardiomyopathy and suggest a genetic basis for the known sex-disparity in Dilated Cardiomyopathy outcomes
Matthew R G Taylor - One of the best experts on this subject based on the ideXlab platform.
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truncations of titin causing Dilated Cardiomyopathy
The New England Journal of Medicine, 2012Co-Authors: Daniel S Herman, Matthew R G Taylor, Lien Lam, Libin Wang, Polakit Teekakirikul, Danos C Christodoulou, Lauren Conner, Steven R Depalma, Barbara Mcdonough, Elizabeth SparksAbstract:Background Dilated Cardiomyopathy and hypertrophic Cardiomyopathy arise from mutations in many genes. TTN, the gene encoding the sarcomere protein titin, has been insufficiently analyzed for Cardiomyopathy mutations because of its enormous size. Methods We analyzed TTN in 312 subjects with Dilated Cardiomyopathy, 231 subjects with hypertrophic Cardiomyopathy, and 249 controls by using next-generation or dideoxy sequencing. We evaluated deleterious variants for cosegregation in families and assessed clinical characteristics. Results We identified 72 unique mutations (25 nonsense, 23 frameshift, 23 splicing, and 1 large tandem insertion) that altered full-length titin. Among subjects studied by means of next-generation sequencing, the frequency of TTN mutations was significantly higher among subjects with Dilated Cardiomyopathy (54 of 203 [27%]) than among subjects with hypertrophic Cardiomyopathy (3 of 231 [1%], P=3×10−16) or controls (7 of 249 [3%], P=9×10−14). TTN mutations cosegregated with Dilated card...
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tafazzin gene mutations are uncommon causes of Dilated Cardiomyopathy in adults
Cardiogenetics, 2011Co-Authors: Matthew R G Taylor, Deborah Ferguson, Jean Jirikowic, Andrea Di Lenarda, Gianfranco Sinagra, Ernesto E. Salcedo, Dobromir Slavov, Luisa MestroniAbstract:Barth syndrome is an X-linked genetic condition featuring neutropenia, skeletal myopathy, and Dilated Cardiomyopathy in boys due to tafazzin (TAZ) mutations. Pure Dilated Cardiomyopathy without other features of Barth syndrome may also result from TAZ mutations and survival into adulthood has been described. Although TAZ testing is routinely included in Dilated Cardiomyopathy panels in adults, the prevalence of TAZ mutations in the adult population, including women who may be at risk to develop later onset disease due to TAZ mutations, has not been measured. We screened 292 families with Dilated Cardiomyopathy (209 male and 83 female probands) for TAZ mutations using denaturing high-performance liquid chromatography and sequence analysis. Putative mutations were evaluated based on standard criteria including screening available relatives and healthy controls and for effects on splicing efficiency in the case of one intronic variant. Two variants suspicious for being pathogenic were found in two unrelated families (c.387T>C, Phe128Ser and c.507C>T, Leu169Leu). The Phe128Ser variant had been previously reported as a pathogenic mutation; however we determined that this variant is instead a rare polymorphism restricted to African Americans. The Leu169Leu variant was detected in a male patient and altered RNA processing in our minigene assay supporting a pathogenic role. No mutations in female subjects were detected. Tafazzin mutations were rare in our population of adults with Dilated Cardiomyopathy and none were found in females. Our findings indicate that genetic testing for tafazzin should not be routinely performed in Dilated Cardiomyopathy as suggested by current guidelines. Furthermore, the Phe128Ser variant is not pathogenic, but likely represents a benign polymorphism in persons of African American ancestry.
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scn5a mutations associate with arrhythmic Dilated Cardiomyopathy and commonly localize to the voltage sensing mechanism
Journal of the American College of Cardiology, 2011Co-Authors: William P Mcnair, Matthew R G Taylor, Andrea Di Lenarda, Gianfranco Sinagra, Ernesto E. Salcedo, Dobromir Slavov, Debra A Ferguson, Xiao Zhu, John H Caldwell, Luisa MestroniAbstract:Objectives: The aim of this study was to discern the role of the cardiac voltage-gated sodium ion channel SCN5A in the etiology of Dilated Cardiomyopathy (DCM).Background: Dilated Cardiomyopathy as...
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prevalence of desmin mutations in Dilated Cardiomyopathy
Circulation, 2007Co-Authors: Matthew R G Taylor, Andrea Di Lenarda, Gianfranco Sinagra, Dobromir Slavov, Debra A Ferguson, Elisa Carniel, Kurt W Haubold, Mark M Boucek, Sharon L Graw, Xiao ZhuAbstract:Background— Desmin-related myofibrillar myopathy (DRM) is a cardiac and skeletal muscle disease caused by mutations in the desmin (DES) gene. Mutations in the central 2B domain of DES cause skeletal muscle disease that typically precedes cardiac involvement. However, the prevalence of DES mutations in Dilated Cardiomyopathy (DCM) without skeletal muscle disease is not known. Methods and Results— Denaturing high-performance liquid chromatography was used to screen DES for mutations in 116 DCM families from the Familial Dilated Cardiomyopathy Registry and in 309 subjects with DCM from the Beta-Blocker Evaluation of Survival Trial (BEST). DES mutations were transfected into SW13 and human smooth muscle cells and neonatal rat cardiac myocytes, and the effects on cytoskeletal desmin network architecture were analyzed with confocal microscopy. Five novel missense DES mutations, including the first localized to the highly conserved 1A domain, were detected in 6 subjects (1.4%). Transfection of DES mutations in t...