Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy (original) (raw)
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Human Mutation, 2009
The American Heart Association (AHA) recommends family screening for hypertrophic cardiomyopathy (HCM). We assessed the outcome of family screening combining clinical evaluation and screening for sarcomere gene mutations in a cohort of 90 Danish HCM patients and their close relatives, in all 451 persons. Index patients were screened for mutations in all coding regions of 10 sarcomere genes (MYH7, MYL3, MYBPC3, TNNI3, TNNT2, TPM1, ACTC, CSRP3, TCAP, and TNNC1) and five exons of TTN. Relatives were screened for presence of minor or major diagnostic criteria for HCM and tracking of DNA variants was performed. In total, 297 adult relatives (>18 years) (51.2%) fulfilled one or more criteria for HCM. A total of 38 HCM-causing mutations were detected in 32 index patients. Six patients carried two disease-associated mutations. Twenty-two mutations have only been identified in the present cohort. The genetic diagnostic yield was almost twice as high in familial HCM (53%) vs. HCM of sporadic or unclear inheritance (19%). The yield was highest in families with an additional history of HCM-related clinical events. In relatives, 29.9% of mutation carriers did not fulfil any clinical diagnostic criterion, and in 37.5% of relatives without a mutation, one or more criteria was fulfilled. A total of 60% of family members had no mutation and could be reassured and further follow-up ceased. Genetic diagnosis may be established in approximately 40% of families with the highest yield in familial HCM with clinical events. Mutation-screening was superior to clinical investigation in identification of individuals not at increased risk, where follow-up is redundant, but should be offered in all families with relatives at risk for developing HCM. Hum Mutat 0,1–8, 2008. © 2008 Wiley-Liss, Inc.
Circulation Journal, 2019
Background: Hypertrophic cardiomyopathy (HCM) is associated primarily with pathogenic mutations in sarcomeric genes. The aim of this study was to identify the prevalence and distribution of disease-causing mutations in HCM-associated genes and the genotypephenotype relationship in Vietnamese patients with HCM. Methods and Results: Genetic testing was performed by next-generation sequencing in 104 unrelated probands for 23 HCMrelated genes and in 57 family members for the mutation(s) detected. Clinical manifestations were recorded for genotype-phenotype correlation analysis. Mutation detection rate was 43.4%. Mutations in MYBPC3 accounted for 38.6%, followed by TPM1 (20.5%), MYH7 (18.2%), TNNT2 (9.1%), TNNI3 (4.5%) and MYL2 (2.3%). A mutation in GLA associated with Fabry disease was found in 1 patient. A mutation in TPM1 (c.842T>C, p.Met281Thr) was identified in 8 unrelated probands (18.2%) and 8 family members from 5 probands. Genotype-positive status related to MYH7, TPM1, and TNNT2 mutations was associated with severe clinical manifestations. MYH7-positive patients displayed worse prognosis compared with MYBPC3-positive patients. Interestingly, TPM1 c.842T>C mutation was associated with high penetrance and severe HCM phenotype. Conclusions: We report for the first time the prevalence of HCM-related gene variants in Vietnamese patients with HCM. MYH7, TPM1, and TNNT2 mutations were associated with unfavorable prognosis.
Acta cardiologica, 2012
Hypertrophic cardiomyopathy (HCM) is a cardiovascular disease with autosomal dominant inheritance. It is caused by mutations in the genes coding for structural and/or regulatory proteins found in the sarcomere of cardiomyocytes. A group of genes, including the heavy chain of beta-myosin (MYH7), myosin binding protein C (MYBPC3), cardiac troponin I (TNNI3) and cardiac troponin T (TNNT2) are frequently affected by causal mutations. While exact mutation frequency data has been obtained for various populations, no screening has been reported for Central European populations. We performed a complete sequencing of MYH7, MYBPC3, TNNI3 and TNNT2 genes in 100 HCM patients. We discovered mutations in a total of 40 patients (40%), including 4 patients with double mutations. A total of 35 different mutation types were detected, of which 17 were novel. The contributions from individual genes were: 24 mutations in MYBPC3 (54.5%), 14 in MYH7 (31.8%), 4 in TNNI3 (9%) and 2 mutations in TNNT2 (4.5%)...
International Journal of Molecular Sciences, 2016
Sequencing of sarcomere protein genes in patients fulfilling the clinical diagnostic criteria for hypertrophic cardiomyopathy (HCM) identifies a disease-causing mutation in 35% to 60% of cases. Age at diagnosis and family history may increase the yield of mutations screening. In order to assess whether Next-Generation Sequencing (NGS) may fulfil the molecular diagnostic needs in HCM, we included 17 HCM-related genes in a sequencing panel run on PGM IonTorrent. We selected 70 HCM patients, 35 with early (ď25 years) and 35 with late (ě65 years) diagnosis of disease onset. All samples had a 98.6% average of target regions, with coverage higher than 20(mean coverage 620ˆ). We identified 41 different mutations (seven of them novel) in nine genes: MYBPC3 (17/41 = 41%); MYH7 (10/41 = 24%); TNNT2, CAV3 and MYH6 (3/41 = 7.5% each); TNNI3 (2/41 = 5%); GLA, MYL2, and MYL3 (1/41=2.5% each). Mutation detection rate was 30/35 (85.7%) in early-onset and 8/35 (22.9%) in late-onset HCM patients, respectively (p < 0.0001). The overall detection rate for patients with positive family history was 84%, and 90.5% in patients with early disease onset. In our study NGS revealed higher mutations yield in patients with early onset and with a family history of HCM. Appropriate patient selection can increase the yield of genetic testing and make diagnostic testing cost-effective.
Genetic Determinants of Clinical Phenotype in Hypertrophic Cardiomyopathy
Research Square (Research Square), 2020
Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease that affects approximately one in 500 people. HCM is a recognized genetic disorder most often caused by mutations involving myosin-binding protein C (MYBPC3) and β-myosin heavy chain (MYH7) which are responsible for approximately three-quarters of the identi ed mutations. Methods: As a part of the international multidisciplinary SILICOFCM project (www.silicofcm.eu) the present study evaluated the association between underlying genetic mutations and clinical phenotype in patients with HCM. Only patients with con rmed single pathogenic mutations in either MYBPC3 or MYH7 genes were included in the study and divided into two groups accordingly. The MYBPC3 group was comprised of 48 patients (76%), while the MYH7 group included 15 patients (24%). Each patient underwent clinical examination and echocardiography. Results: The most prevalent symptom in patients with MYBPC3 was dyspnea (44%), whereas in patients with MYH7 it was palpitations (33%). The MYBPC3 group had a signi cantly higher number of patients with a positive family history of HCM (46% vs. 7%; p=0.014). There was a numerically higher prevalence of atrial brillation in the MYH7 group (60% vs. 35%, p=0.085). Laboratory analyses revealed normal levels of creatinine (85.5±18.3 vs. 81.3±16.4 µmol/l; p=0.487) and blood urea nitrogen (10.2±15.6 vs. 6.9±3.9 mmol/l; p=0.472) which were similar in both groups. The systolic anterior motion presence was signi cantly more frequent in patients carrying MYH7 mutation (33% vs. 10%; p=0.025), as well as mitral lea et abnormalities (40% vs. 19%; p=0.039). Calci cations of mitral annulus were registered only in MYH7 patients (20% vs. 0%; p=0.001). The difference in diastolic function, i.e. E/e' ratio between the two groups was also noted (MYBPC3 8.8±3.3, MYH7 13.9±6.9, p=0.079). Conclusions: Major ndings of the present study corroborate the notion that MYH7 gene mutation patients are presented with more pronounced disease severity than those with MYBPC3.
Genetic Determinants Of Clinical Phenotype In Hypertrophic Cardiomyopathy 
Research Square (Research Square), 2020
Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease that affects approximately one in 500 people. HCM is a recognized genetic disorder most often caused by mutations involving myosin-binding protein C (MYBPC3) and β-myosin heavy chain (MYH7) which are responsible for approximately three-quarters of the identi ed mutations. Methods: As a part of the international multidisciplinary SILICOFCM project (www.silicofcm.eu) the present study evaluated the association between underlying genetic mutations and clinical phenotype in patients with HCM. Only patients with con rmed single pathogenic mutations in either MYBPC3 or MYH7 genes were included in the study and divided into two groups accordingly. The MYBPC3 group was comprised of 48 patients (76%), while the MYH7 group included 15 patients (24%). Each patient underwent clinical examination and echocardiography. Results: The most prevalent symptom in patients with MYBPC3 was dyspnea (44%), whereas in patients with MYH7 it was palpitations (33%). The MYBPC3 group had a signi cantly higher number of patients with a positive family history of HCM (46% vs. 7%; p=0.014). There was a numerically higher prevalence of atrial brillation in the MYH7 group (60% vs. 35%, p=0.085). Laboratory analyses revealed normal levels of creatinine (85.5±18.3 vs. 81.3±16.4 µmol/l; p=0.487) and blood urea nitrogen (10.2±15.6 vs. 6.9±3.9 mmol/l; p=0.472) which were similar in both groups. The systolic anterior motion presence was signi cantly more frequent in patients caring MYH7 mutation (33% vs. 10%; p=0.025), as well as mitral lea et abnormalities (40% vs. 19%; p=0.039). Calci cations of mitral annulus were registered only in MYH7 patients (20% vs. 0%; p=0.001). The difference in diastolic function, i.e. E/e' ratio between the two groups was also noted (MYBPC3 8.8±3.3, MYH7 13.9±6.9, p=0.079). Conclusions: Major ndings of the present study corroborate the notion that MYH7 gene mutation patients are presented with more pronounced disease severity than those with MYBPC3.
A Nationwide Study on Hypertrophic Cardiomyopathy in Iceland: Evidence of a MYBPC3 Founder Mutation
H ypertrophic cardiomyopathy (HCM) is a primary myocardial disorder characterized by unexplained left ventricular (LV) hypertrophy in the absence of other predisposing clinical conditions. 1 Mutations in the protein components of the sarcomere cause HCM. Hypertrophic remodeling also occurs in disorders that clinically mimic HCM, including Fabry disease (GLA mutations), glycogen cardiomyopathy (PRKAG2 mutations), and Danon disease (LAMP2 mutations). 2 More than 1400 different mutations in at least 8 sarcomere protein genes have been reported in HCM. 3,4 Even though a majority (≈80%) of HCM mutations alter the cardiac β-myosin heavy chain (MYH7) or cardiac myosin binding protein-C (MYBPC3) gene, 5 most are "private" and unique to a specific family. The diverse molecular origin of HCM, combined with background genomic variability and lifestyle differences among patients with HCM, has hindered definitive insights into genotype and phenotype relationships. 3-6 Clinical Perspective on p 1167 Background-The geographic isolation and homogeneous population of Iceland are ideally suited to ascertain clinical and genetic characteristics of hypertrophic cardiomyopathy (HCM) at the population level. Methods and Results-Medical records and cardiac imaging studies obtained between 1997 and 2010 were reviewed to identify Icelandic patients with HCM. Surviving patients were recruited for clinical and genetic studies. A previously identified Icelandic mutation, MYBPC3 c.927-2A>G, was genotyped, and mutation-negative samples were sequenced for HCM genes and other hypertrophic genes. Record review identified 180 patients with HCM. Genetic analyses of 151 patients defined pathogenic mutations in 101 (67%), including MYBPC3 c.927-2A>G (88 patients, 58%), 4 other MYBPC3 or MYH7 mutations (5 patients, 3.3%), and 2 GLA mutations (8 patients, 5.3%). Haplotype and genetic genealogical data defined MYBPC3 c.927-2A>G as a founder mutation, introduced into the Icelandic population in the 15th century, with a current population prevalence of 0.36%. MYBPC3 c.927-2A>G mutation carriers exhibited phenotypic diversity but were younger at diagnosis (42 versus 49 years; P=0.001) and sustained more adverse events (15% versus 2%; P=0.02) than mutation-negative patients. All-cause mortality for patients with HCM was similar to that of an age-matched Icelandic population (hazard ratio, 0.98; P=0.9). HCM-related mortality (0.78%/y) occurred at a mean age of 68 compared with 81 years for non-HCM-related mortality (P=0.02). Conclusions-A founder MYBPC3 mutation that arose >550 years ago is the predominant cause of HCM in Iceland. The MYBPC3 c.927-2A>G mutation is associated with low adverse event rates but earlier cardiovascular mortality, illustrating the impact of genotype on outcomes in HCM.
Anadolu Kardiyoloji Dergisi/The Anatolian Journal of Cardiology, 2014
Objective: Hypertrophic cardiomyopathy (HCM) is a disease of the myocardium with an autosomal-dominant pattern of inheritance mainly caused by single heterozygous mutations in sarcomere genes. In this study we aimed to detect the presence of R403QLW, V606M, K615N, and R663H mutations in beta-myosin heavy-chain gene (MYH7) and figure out the genotype-phenotype correlations in Turkish patients with HCM. Methods: This case-control study based on genotype-phenotype correlation included 69 patients (mean age, years: 50±13.16) diagnosed with HCM constituting the study group and 50 healthy individuals (mean age, years: 52±1.4) constituting the control group. DNA was extracted from peripheral blood and the genotyping of mutations was performed by real-time PCR technique and high resolution melting analysis. Associations between categoric variables were determined using chi-square tests. Differences between two groups were compared with unpaired Student's t-test for continuous variables. Results: None of the patients in the HCM group were carrying the index mutations. One healthy individual was found to be heterozygous for the R663H mutation with mildly abnormal IVS and LVPW thickness. The allele frequency for R663H (G>A) mutation was found to be 0.01% in control group. Conclusion: We performed a mutational screening of 6 HCM-associated mutations in 69 Turkish HCM patients (not previously studied except R403Q). There was no significant difference in the prevalence of the mutations between the patients with HCM and the healthy controls (p>0.05). (Anadolu Kardiyol Derg 2014; 14: 244-50)