Genetic screening of calcium regulation genes in familial hypertrophic cardiomyopathy

Chiu, Christine L; Tebo, Molly; Ingles, Jodie; Yeates, Laura; Arthur, Jonathan W.; Lind, Joanne M.; Semsarian, Christopher

doi:10.1016/j.yjmcc.2007.06.009

Cited by 69 publications

(58 citation statements)

References 28 publications

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“…Pathogenicity was assessed on the basis of the following criteria, as previously described: (i) a nonsynonymous variant that causes an amino acid change that is conserved among species; (ii) the variant is not present in healthy control populations, including the 1000 Genomes and dbSNP databases with a minor allele frequency of <0.01; (iii) there is cosegregation with affected family members; and/or (iv) it has been previously reported as a causative HCM mutation. 22,23 This information was evaluated by the attending cardiologist and/or clinical geneticists on a case-by-case basis as part of the clinical service, and accordingly used for predictive testing where indicated.…”

Section: Genetic Testingmentioning

confidence: 99%

Clinical predictors of genetic testing outcomes in hypertrophic cardiomyopathy

Ingles

Sarina

Yeates

et al. 2013

Genetics in Medicine

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Purpose: Genetic testing for hypertrophic cardiomyopathy has been commercially available for almost a decade; however, low mutation detection rate and cost have hindered uptake. This study sought to identify clinical variables that can predict probands with hypertrophic cardiomyopathy in whom a pathogenic mutation will be identified. Methods:Probands attending specialized cardiac genetic clinics across Australia over a 10-year period (2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011), who met clinical diagnostic criteria for hypertrophic cardiomyopathy and who underwent genetic testing for hypertrophic cardiomyopathy were included. Clinical, family history, and genotype information were collected.Results: A total of 265 unrelated individuals with hypertrophic cardiomyopathy were included, with 138 (52%) having at least one mutation identified. The mutation detection rate was significantly higher in the probands with hypertrophic cardiomyopathy with an established family history of disease (72 vs. 29%, P < 0.0001), and a positive family history of sudden cardiac death further increased the detection rate (89 vs. 59%, P < 0.0001). Multivariate analysis identified female gender, increased left-ventricular wall thickness, family history of hypertrophic cardiomyopathy, and family history of sudden cardiac death as being associated with greatest chance of identifying a gene mutation. Multiple mutation carriers (n = 16, 6%) were more likely to have suffered an out-of-hospital cardiac arrest or sudden cardiac death (31 vs. 7%, P = 0.012). Conclusion:Family history is a key clinical predictor of a positive genetic diagnosis and has direct clinical relevance, particularly in the pretest genetic counseling setting.

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Section: Genetic Testingmentioning

confidence: 99%

Clinical predictors of genetic testing outcomes in hypertrophic cardiomyopathy

Ingles

Sarina

Yeates

et al. 2013

Genetics in Medicine

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123

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“…96,97 In contrast, a truncation mutation of PLN, that is loss of PLN function, is recently reported in familial HCM. 98 Although PLN deficiency in mice resulted in enhanced contractility, 99 no cardiac hypertrophy was observed in the mice. In addition, loss of PLN rescued DCM phenotype 100 in MLP knock-out mice, and a dominant-negative form of PLN prevented heart failure in cardiomyopathic hamster BIO14.6, 101 which is known to be caused by SAGD deficiency.…”

Section: Other Mutations In Dcmmentioning

confidence: 99%

Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond

Kimura

2010

J Hum Genet

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Cardiomyopathy is caused by functional abnormality of cardiac muscle. The functional abnormality involved in its etiology includes both extrinsic and intrinsic factors, and cardiomyopathy caused by the intrinsic factors is called as idiopathic or primary cardiomyopathy. There are several clinical types of primary cardiomyopathy including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Linkage studies and candidate gene approaches have explored the disease genes for hereditary primary cardiomyopathy. The most notable finding was that mutations in the same disease gene can be found in different clinical types of cardiomyopathy. Functional analyses of disease-related mutations have revealed that characteristic functional alterations are associated with the clinical types, such that increased and decreased Ca 2+ sensitivity due to sarcomere mutations are associated with HCM and DCM, respectively. In addition, our recent studies have suggested that mutations in the Z-disc components found in HCM and DCM may result in increased and decreased stiffness of sarcomere; that is, stiff sarcomere and loose sarcomere, respectively, and hence altered stretch response. More recently, mutations in the components of I region were found in hereditary cardiomyopathy and the functional analyses of the mutations suggested that the altered stress response was associated with cardiomyopathy, further complicating the etiology and pathogenesis. However, elucidation of genetic etiology and functional alterations caused by the mutations shed lights on the new therapeutic approaches to hereditary cardiomyopathy, such that treatment of DCM with a Ca 2+ sensitizer prevented the disease in a mouse model.

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“…HCM is the most common inherited cardiomyopathy (population frequency, 1:500), is characterized by cardiac hypertrophy and diastolic dysfunction that typically develops over many years, and can be complicated by heart failure, arrhythmias, and sudden cardiac death (33,48,57). The majority of HCM cases are linked to autosomal dominant mutations in cardiac sarcomere genes, with a small percentage of others associated with mutations in Z-disc, metabolic, and Ca 2ϩ -handling genes (1,15,32,47,49,50,64,73). Roughly, two-thirds of HCM patients develop LV outflow tract obstruction (51), and a small, but important, subset of these patients have symptoms refractory to medical therapy, necessitating surgical resection of muscle in the basal portion of the intraventricular septum, referred to as a septal myectomy (17,55).…”

Section: Human Cardiomyopathies: Etiologies and Clinical Featuresmentioning

confidence: 99%