Ingles, J., Doolan, A., Chiu, C., Seidman, J., Seidman, C. & Semsarian, C. Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling. J. Med. Genet. 42, e59

Journal of Medical Genetics (Impact Factor: 6.34). 10/2005; 42(10):e59. DOI: 10.1136/jmg.2005.033886
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To report the frequency of single and multiple gene mutations in an Australian cohort of patients with hypertrophic cardiomyopathy (HCM).
Genetic screening of seven HCM genes (beta-MHC, MyBP-C, cTnT, cTnI, ACTC, MYL2, and MYL3) was undertaken in 80 unrelated probands. Screening was by denaturing high performance liquid chromatography and direct DNA sequencing. Clinical data were collected on all patients and on genotyped family members.
26 mutations were identified in 23 families (29%). Nineteen probands (24%) had single mutations (11 beta-MHC, 4 MyBP-C, 3 cTnI, 1 cTnT). Multiple gene mutations were identified in four probands (5%): one had a double mutation and the others had compound mutations. Six of 14 affected individuals from multiple mutation families (43%) experienced a sudden cardiac death event, compared with 10 of 55 affected members (18%) from single mutation families (p = 0.05). There was an increase in septal wall thickness in patients with compound mutations (mean (SD): 30.7 (3.1) v 24.4 (7.4) mm; p<0.05).
Multiple gene mutations occurring in HCM families may result in a more severe clinical phenotype because of a "double dose" effect. This highlights the importance of screening the entire panel of HCM genes even after a single mutation has been identified.

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Available from: Christopher Semsarian, Mar 10, 2014
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    • "Compound heterozygosity (double and triple mutations) had been reported to cause HCM phenotype [18], [19]. Therefore, we have further analyzed the patient and three of his family members carrying R144W mutation having DCM phenotype with eight other genes (β-MYH7, MYBPC3, TPM1, TNNI3, TTN, ACTC, MYL2 and MYL3), to rule out compound heterozygosity. "
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    ABSTRACT: Cardiomyopathy is a major cause of heart failure and sudden cardiac death; several mutations in sarcomeric protein genes have been associated with this disease. Our aim in the present study is to investigate the genetic variations in Troponin T (cTnT) gene and its association with dilated cardiomyopathy (DCM) in south-Indian patients. Analyses of all the exons and exon-intron boundaries of cTnT in 147 DCM and in 207 healthy controls had revealed a total of 15 SNPs and a 5 bp INDEL; of which, polymorphic SNPs were compared with the HapMap population data. Interestingly, a novel R144W mutation, that substitutes polar-neutral tryptophan for a highly conserved basic arginine in cTnT, altering the charge drastically, was identified in a DCM, with a family history of sudden-cardiac death (SCD). This mutation was found within the tropomyosin (TPM1) binding domain, and was evolutionarily conserved across species, therefore it is expected to have a significant impact on the structure and function of the protein. Family studies had revealed that the R144W is co-segregating with disease in the family as an autosomal dominant trait, but it was completely absent in 207 healthy controls and in 162 previously studied HCM patients. Further screening of the proband and three of his family members (positive for R144W mutant) with eight other genes β-MYH7, MYBPC3, TPM1, TNNI3, TTN, ACTC, MYL2 and MYL3, did not reveal any disease causing mutation, proposing the absence of compound heterozygosity. Therefore, we strongly suggest that the novel R144W unique/private mutant identified in this study is associated with FDCM. This is furthermore signifying the unique genetic architecture of Indian population.
    PLoS ONE 07/2014; 9(7):e101451. DOI:10.1371/journal.pone.0101451 · 3.23 Impact Factor
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    • "Some patients harbor more than one pathogenic mutation and the literature so far estimates that it occurs in 3-5% of the patients24-26. According to Kelly and Semsarian27, the clinical features in patients with more than one mutation are more severe, with greater risk of sudden death and LV hypertrophy. "
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    ABSTRACT: Hypertrophic cardiomyopathy (HCM) is the most common monogenic genetic cardiac disease, with an estimated prevalence of 1:500 in the general population. Clinically, HCM is characterized by hypertrophy of the left ventricle (LV) walls, especially the septum, usually asymmetric, in the absence of any cardiac or systemic disease that leads to a secondary hypertrophy. The clinical course of the disease has a large inter- and intrafamilial heterogeneity, ranging from mild symptoms of heart failure late in life to the onset of sudden cardiac death at a young age and is caused by a mutation in one of the genes that encode a protein from the sarcomere, Z-disc or intracellular calcium modulators. Although many genes and mutations are already known to cause HCM, the molecular pathways that lead to the phenotype are still unclear. This review focus on the molecular mechanisms of HCM, the pathways from mutation to clinical phenotype and how the disease's genotype correlates with phenotype.
    Arquivos brasileiros de cardiologia 03/2014; 102(3):295-304. DOI:10.5935/abc.20140022 · 1.02 Impact Factor
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    • "e l s e v i e r . c o m / l o c a t e / y j m c c phenotype, severe heart failure and premature mortality [7] [8]. In brief, by age 2 weeks, HCM mice develop significant myocardial fibrosis, and subsequently progress to a severe dilated cardiomyopathy, heart failure, and 100% mortality by age 3 weeks. "
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    ABSTRACT: Hypertrophic cardiomyopathy (HCM) is the most common inherited primary myocardial disorder. HCM is characterized by interstitial fibrosis and excessive accumulation of extracellular matrix (ECM) proteins. Fibrosis in HCM has been associated with impaired cardiac function and heart failure, and has been considered a key substrate for ventricular arrhythmias and sudden death. The molecular triggers underpinning ECM production are not well established. We have previously developed a double-mutant mouse model of HCM that recapitulates the phenotype seen in humans with multiple mutations, including earlier onset of the disease, progression to a dilated phenotype, severe heart failure and premature mortality. The present study investigated the expression of ECM-encoding genes in severe HCM and heart failure. Significant upregulation of structural Fn1, regulatory Mmp14, Timp1, Serpin3A, SerpinE1, SerpineE2, Tgfβ1, Tgfβ2; and matricellular Ccn2, Postn, Spp1, Thbs1, Thbs4, Tnc was evident from the early, pre-phenotype stage. Non-myocytes expressed ECM genes at higher levels than cardiomyocytes in normal and diseased hearts. Synchronous increase of secreted CCN2 and TIMP1 plasma levels and decrease of MMP3 levels was observed in end-stage disease. CCN2 protein expression was increased from early disease in double-mutant hearts and played an important role in ECM responses. It was a powerful modulator of ECM regulatory (Timp1 and SerpinE1) and matricellular protein-encoding (Spp1, Thbs1, Thbs4 and Tnc) gene expression in cardiomyocytes when added exogenously in vitro. Modulation of CCN2 (CTGF, connective tissue growth factor) and associated early ECM changes may represent a new therapeutic target in the treatment and prevention of heart failure in HCM.
    Journal of Molecular and Cellular Cardiology 06/2013; 22. DOI:10.1016/j.yjmcc.2013.05.019 · 4.66 Impact Factor
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