G2Cdb::Human Disease report

Disease id
D00000235
Name
Hypertrophic cardiomyopathy
Nervous system disease
no

Genes (3)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00002000 MYO5A
myosin VA (heavy chain 12, myoxin)
Y (1361491) Deletion (D) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (15010274) Polymorphism (P) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (15358028) Microinsertion (MI) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (15358028) Deletion (D) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (15563892) Polymorphism (P) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (15569455) Unknown (?) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (15706574) Single nucleotide polymorphism (SNP) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (15769782) Microinsertion (MI) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (15819282) Unknown (?) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (15856146) Microinsertion (MI) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (15940186) Polymorphism (P) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (16137545) Single nucleotide polymorphism (SNP) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (16504640) Polymorphism (P) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (16630449) Single nucleotide polymorphism (SNP) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (16650083) Microinsertion (MI) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (16858239) Microinsertion (MI) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (16938236) Single nucleotide polymorphism (SNP) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (17097032) Single nucleotide polymorphism (SNP) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (17125710) Single nucleotide polymorphism (SNP) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (17288815) Single nucleotide polymorphism (SNP) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (17288815) Microinsertion (MI) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (17347475) No mutation found (N) N
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (14991917) Single nucleotide polymorphism (SNP) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15578621) Polymorphism (P) N
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15889278) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (16488201) No mutation found (N) N

References

  • Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy.

    Osio A, Tan L, Chen SN, Lombardi R, Nagueh SF, Shete S, Roberts R, Willerson JT and Marian AJ

    Center for Cardiovascular Genetic Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Sciences Center, Houston, TX 77030, USA.

    Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in sarcomeric proteins (excluding phenocopy). The causal genes in approximately one-third of the cases remain unknown. We identified a family comprised of 6 clinically affected members. The phenotype was characterized by early onset of symptoms, pronounced cardiac hypertrophy, and cardiac arrhythmias. We excluded MYH7, MYBPC3, TNNT2, and ACTC1 as the causal gene either by direct sequencing or by haplotype analysis. To map the putative candidate sarcomeric gene, we perforbold locus-specific haplotyping to detect cosegregation of the locus haplotype with the phenotype, followed by mutation screening. We genotyped 5 short-tandem-repeat markers that spanned a 4.4-centimorgan region on 4q26-q27 locus and encompassed myozenin 2 (MYOZ2), a Z-disk protein. The maximum logarithm of odds score was 2.03 (P=0.005). All affected members shared a common haplotype, implicating MYOZ2 as the causal gene. To detect the causal mutation, we sequenced all exons and exon-intron boundaries of MYOZ2 in 10 family members and identified a T-->C missense mutation corresponding to S48P substitution, which cosegregated with inheritance of HCM (N=6). It was absent in 4 clinically normal family members and in 658 additional normal individuals. To determine frequency of the MYOZ2 mutations in HCM, we sequenced MYOZ2 in 516 HCM probands and detected another missense mutation (I246M). It was absent in 2 normal family members and 517 controls. Both mutations affect highly conserved amino acids. We conclude MYOZ2 is a novel causal gene for human HCM.

    Funded by: NHLBI NIH HHS: P50 HL054313, P50 HL054313-060012, P50 HL054313-070012, P50 HL054313-080012, P50 HL054313-08S10012, P50 HL054313-090012, P50 HL054313-100012, R01 HL068884, R01 HL068884-01, R01 HL068884-02, R01 HL068884-03, R01 HL068884-04, R01 HL068884-05, R01-HL68884

    Circulation research 2007;100;6;766-8

  • [Comparative study of gene mutation between Chinese patients with familial and sporadic hypertrophic cardiomyopathy].

    Pan GZ, Liu WL, Hu DY, Xie WL, Zhu TG, Li L, Li CL and Bian H

    Department of Cardiology, Fuxing Hospital Affiliated to Capital University of Medical Sciences, Beijing 100038, China.

    Objective: To compare the gene mutation between Chinese patients with familial and sporadic hypertrophic cardiomyopathy (HCM).

    Methods: Peripheral blood samples were collected from 36 patients with familial HCM (FHCM) and 50 patients with sporadic HCM (SHCM), all un-related and from different provinces of China. PCR was used to amplify the 26 protein-coding axons of beta-myosin heavy chain (MYH7), 16 exons for cardiac troponin T (TNNT2), and 38 exons for cardiac myosin-binding protein C (MYBPC3). The amplified products were sequenced and compared with the standard sequence in the genBank so as to determine the potential mutation sites.

    Results: (1) 13 of the 36 FHCM patients (36.1%) harbored 3 different mutations in MYH7 gene: Arg663His in exon18, Glu924Lys in exon 23, and Ile736Thr in exon 20. Of the 50 SHCM patients, only 1 (2%) harbored MYH7 gene missence mutation: Ile736Thr located in exon 20. (2) TNNT2 was not identified in all SHCM patients and FHCM patients. (3) MYBPC3 was not identified in all SHCM patients. Four FHCM patients harbored 2 different mutations: Arg502Trp in exon 18 and Arg346fs in exon 13 respectively.

    Conclusion: MYH7 and MYBPC3 may be the dominant disease-causing genes in Chinese familial HCM patients; however the mutation rate of MYH7 and MYBPC3 genes is significantly lower in the SHCM patients compared with the FHCM patients. TNNT2 seems not the predominant disease-causing gene in all Chinese patients with HCM.

    Zhonghua yi xue za zhi 2006;86;42;2998-3001

  • Mutation of Arg723Gly in beta-myosin heavy chain gene in five Chinese families with hypertrophic cardiomyopathy.

    Yang JH, Zheng DD, Dong NZ, Yang XJ, Song JP, Jiang TB, Cheng XJ, Li HX, Zhou BY, Zhao CM and Jiang WP

    Department of Cardiology, First Affiliated Hospital of Soochow University, Suzhou 215006, China. yangjhsz@163.com

    Background: Hypertrophic cardiomyopathy (HCM) is a form of cardiomyopathy with an autosomal dominant inherited disease, which is caused by mutations in at least one of the sarcomeric protein genes. Mutations in the beta-myosin heavy chain (beta-MHC) are the most common cause of HCM. This study was to reveal the disease-causing gene mutations in Chinese population with HCM, and to analyze the correlation between the genotype and phenotype.

    Methods: The exons 3 to 26 of MYH7 were amplified by PCR, and the PCR products were sequenced in five non-kin HCM patients. A 17-year-old patient was detected to be an Arg723Gly mutation carrier. Then his family was gene-screened, and the correlation between genotype and phenotype was analyzed.

    Results: The mutation of Arg723Gly in a Chinese family with HCM was detected for the first time. With a C-G transversion in nucleotide 13,619 of the MYH7 gene, located at the essential light chain interacting region in S1, the replacement of arginine by glycine took place at amino acid residue 723. A two-dimensional echocardiogram showed moderate asymmetrical septal hypertrophy with left atria enlargement. There was no obstruction in the left ventricular outflow tract. In his family, a total of 13 individuals were diagnosed HCM and 5 of them were dead of congestive heart failure at a mean age of 66-year-old. Eight living members were all detected to carry the mutation, in which 3 developed progressive heart failure. Moreover, the heart function of the people evidently deteriorates when their age are older than 50. The mutation and the disease show co-separated.

    Conclusion: The Arg723Gly mutation is a malignant type. In Chinese the mutation has the similar characters to the former report but has low degree malignant.

    Chinese medical journal 2006;119;21;1785-9

  • [Beta-myosin heavy-chain gene mutations in patients with hypertrophic cardiomyopathy].

    Laredo R, Monserrat L, Hermida-Prieto M, Fernández X, Rodríguez I, Cazón L, Alvariño I, Dumont C, Piñón P, Peteiro J, Bouzas B and Castro-Beiras A

    Servicio de Cardiología, Complejo Hospitalario Universitario Juan Canalejo e Instituto Universitario de Ciencias de la Salud de la Universidad de A Coruña, A Coruña, Spain.

    To determine the frequency of mutations in the beta-myosin heavy-chain gene (MYH7) in a cohort of patients with hypertrophic cardiomyopathy (HCM) and their families, and to investigate correlations between genotype and phenotype.

    Methods: Single-strand conformation polymorphism analysis and sequencing of fragments with abnormal MYH7 gene mobility were carried out in 128 consecutive index patients with HCM. The phenotypes of patients with and without mutations were compared and the phenotypes of identified families were recorded.

    Results: A total of 11 mutations were found in 13 families (10%); 7/11 had been previously described. The I736T mutation was found in three families and the A797T in two. One patient had two mutations (i.e., I736T and R787H). Mutations were more frequent in patients with a family history of sudden death (31%) and in those with severe hypertrophy (39% had a thickness > or = 30 mm). Mutations were found in 29 of 42 members of the 13 families, including six family members (20%) who were healthy carriers and aged < or = 36 years. Sudden death had occurred in eight members of four families: four in two families with the I736T mutation, one in a family with A797T, one in a family with R870H, and two in a family with A901P.

    Conclusions: MYH7 mutations were present in 10% of our families. Mutations were more frequent in patients with a family history of sudden death and in those with severe hypertrophy. Most mutations had been described previously. Some appeared in several families. For some mutations, the correlation between genotype and phenotype was stable, while for others, there were marked differences between the phenotypes of the index patients and their relatives, suggesting the presence of additional genetic factors that have yet to be identified.

    Revista espanola de cardiologia 2006;59;10;1008-18

  • Mutation screening of the PTPN11 gene in hypertrophic cardiomyopathy.

    Limongelli G, Hawkes L, Calabro R, McKenna WJ and Syrris P

    Department of Medicine, University College London and University College London Hospitals Trust, Cobbold Laboratories, 7th Floor, Jules Thorn Institute, Middlesex Hospital, 48 Riding House Street, London W1W 7EY, UK.

    Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease and a major cause of sudden death. It is an autosomal dominant disorder predominantly caused by mutations in genes encoding for sarcomeric proteins. Only 50-60% of HCM probands have mutations in known genes suggesting the presence of additional disease genes. Noonan and LEOPARD syndromes are characterised by multiple dysmorphia and cardiac defects with HCM present in approximately 20% of cases. Both syndromes are caused by mutations in the PTPN11 gene which codes for the protein tyrosine phosphatase SHP-2. It is suspected but unproven that the cardiac phenotype may predominate or even be present in isolation. In order to determine possible involvement of this gene in the pathogenesis of HCM, we performed mutation screening of the PTPN11 coding region in 250 selected HCM probands (200 patients without mutations in sarcomeric genes and 50 with identified mutations). No mutations in PTPN11 were identified. Our data suggests that mutations in the PTPN11 gene are not a cause of HCM in the absence of Noonan/LEOPARD syndromes.

    European journal of medical genetics 2006;49;5;426-30

  • A molecular screening strategy based on beta-myosin heavy chain, cardiac myosin binding protein C and troponin T genes in Italian patients with hypertrophic cardiomyopathy.

    Girolami F, Olivotto I, Passerini I, Zachara E, Nistri S, Re F, Fantini S, Baldini K, Torricelli F and Cecchi F

    Genetic Diagnostic Unit, Azienda Ospedaliero Universitaria Careggi, Florence, Italy. citogenbibl3@ao-careggi.toscana.it

    Background: Mutations causing hypertrophic cardiomyopathy (HCM) have been described in nine different genes of the sarcomere. Three genes account for most known mutations: beta-myosin heavy chain (MYH7), cardiac myosin binding protein C (MYBPC3) and cardiac troponin T (TNNT2). Their prevalence in Italian HCM patients is unknown. Thus, we prospectively assessed a molecular screening strategy of these three genes in a consecutive population with HCM from two Italian centres.

    Methods: Comprehensive screening of MYBPC3, MYH7 and TNNT2 was performed in 88 unrelated HCM patients by denaturing high-performance liquid chromatography and automatic sequencing.

    Results: We identified 32 mutations in 50 patients (57%); 16 were novel. The prevalence rates for MYBPC3, MYH7 and TNNT2 were 32%, 17% and 2%, respectively. MYBPC3 mutations were 18, including two frameshift, five splice-site and two nonsense. All were 'private' except insC1065 and R502Q, present in three and two patients, respectively. Moreover, E258K was found in 14% of patients, suggesting a founder effect. MYH7 mutations were 12, all missense; seven were novel. In TNNT2, only two mutations were found. In addition, five patients had a complex genotype [i.e. carried a double MYBPC3 mutation (n = 2), or were double heterozygous for mutations in MYBPC3 and MYH7 (n = 3)].

    Conclusions: The first comprehensive evaluation of MYBPC3, MYH7 and TNNT2 in an Italian HCM population allowed a genetic diagnosis in 57% of the patients. These data support a combined analysis of the three major sarcomeric genes as a rational and cost-effective initial approach to the molecular screening of HCM.

    Journal of cardiovascular medicine (Hagerstown, Md.) 2006;7;8;601-7

  • [Hypertrophic cardiomyopathy: infrequent mutation of the cardiac beta-myosin heavy-chain gene].

    Mora R, Merino JL, Peinado R, Olias F, García-Guereta L, del Cerro MJ, Tarín MN and Molano J

    Unidad de Genética Molecular, Servicio de Bioquímica, Hospital Universitario La Paz, Madrid, España.

    The aim of this study was to identify mutations in the cardiac heavy-chain beta-myosin gene (MYH7b) in a group of Spanish patients with hypertrophic cardiomyopathy. The study included 36 families with at least one member who had hypertrophic cardiomyopathy. DNA from exons 3 to 24 of the MYH7b gene was sequenced. Two mutations were identified: Arg858Cys and Met515Val. They occurred in two families, one of which was of Moroccan origin. This corresponds to a MYH7b gene mutation frequency of less than 5%. In contrast to findings in other Caucasian populations, MYH7b gene mutation occurred infrequently in this group of Spanish families with hypertrophic cardiomyopathy.

    Revista espanola de cardiologia 2006;59;8;846-9

  • Genotype-phenotype correlation of R870H mutation in hypertrophic cardiomyopathy.

    Tanjore RR, Sikindlapuram AD, Calambur N, Thakkar B, Kerkar PG and Nallari P

    Clinical genetics 2006;69;5;434-6

  • [Analysis of MYH7, MYBPC3 and TNNT2 gene mutations in 10 Chinese pedigrees with familial hypertrophic cardiomyopathy and the correlation between genotype and phenotype].

    Liu WL, Xie WL, Hu DY, Zhu TG, Li YT, Sun YH, Li CL, Li L, Li TC, Bian H, Tong QG, Yang SN, Fan RY and Cui W

    Cardiology Division, People's Hospital, Peking University, Beijing 100044, China.

    Objective: The aim of this study was to screen the disease-causing gene mutations and investigate the genotype-phenotype correlation in 10 Chinese pedigrees with familial hypertrophic cardiomyopathy (HCM).

    Methods: There are 91 family members from these 10 pedigrees and 5 members were normal mutated carriers, 23 members were HCM patients (14 male) aged from 1.5 to 73 years old. The functional regions of myosin heavy chain gene (MYH7), cardiac myosin-binding protein C (MYBPC3) and cardiac troponin T gene (TNNT2) were screened with PCR and direct sequencing technique. Clinical information from all patients was also evaluated in regard to the genotype.

    Results: Mutations were found in 5 out of 10 pedigrees. Mutations in MYH7 (Arg663His, Glu924Lys and Ile736Thr) were found in 3 pedigrees and 3 patients from these pedigrees suffered sudden death at age 20-48 years old during sport. Mutations in MYBPC3 were found in 2 pedigrees, 1 with complex mutation (Arg502Trp and splicing mutation IVS27 + 12C > T) and 1 with novel frame shift mutation (Gly347fs) and the latter pedigree has sudden death history. No mutation was identified in TNNT2.

    Conclusions: Although the Han Chinese is a relatively homogeneous ethnic group, different HCM gene mutations were responsible for familiar HCM suggesting the heterogeneity nature of the disease-causing genes and HCM MYH7 mutations are associated with a higher risk of sudden death in this cohort. Furthermore, identical mutation might result in different phenotypes suggesting that multiple factors might be involved in the pathogenesis of familiar HCM.

    Zhonghua xin xue guan bing za zhi 2006;34;3;202-7

  • Diastolic dysfunction without left ventricular hypertrophy is an early finding in children with hypertrophic cardiomyopathy-causing mutations in the beta-myosin heavy chain, alpha-tropomyosin, and myosin-binding protein C genes.

    Poutanen T, Tikanoja T, Jääskeläinen P, Jokinen E, Silvast A, Laakso M and Kuusisto J

    Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland. tuija.poutanen@koti.tpo.fi

    Objectives: We investigated the presence of left ventricular hypertrophy (LVH) and features of diastolic dysfunction in genotype-confirmed children from families with hypertrophic cardiomyopathy (HCM) and healthy control children.

    Background: In subjects with HCM-causing mutations, LVH usually does not evolve until adolescence. Diastolic dysfunction has not been systematically evaluated in children carrying HCM-causing mutations.

    Methods: All children (aged 1.5-16.7 years) from 14 HCM families with identified disease-causing mutations (the Arg719Trp mutation in the beta-myosin heavy chain gene [MYH7], the Asp175Asn mutation in the alpha-tropomyosin gene [TPM1], the Gln1061X mutation in the myosin-binding protein C gene [MYBPC3], and the IVS5-2A-->C mutation in the MYBPC3 gene) and 53 matched control children were examined with electrocardiography and 2- and 3-dimensional echocardiography (2DE and 3DE). Natriuretic peptides were measured in children from HCM families and 67 control children.

    Results: Of 53 children from HCM families, 27 (51%) had a disease-causing mutation (G+). G+ children had slightly thicker septum on 2DE compared with the control children (P = .004), but only 3 (11%) of 27 G+ children exceeded the 95th percentile values of the body surface area-adjusted maximal LV thickness of healthy children (the major echocardiographic criterion for HCM). However, prolonged isovolumetric relaxation time, increased left atrial volume on 3DE, or increased levels of NT-proANP, all features suggestive of diastolic dysfunction, were found in 14 (52%) of 27 G+ children.

    Conclusions: In children with HCM-causing mutations, signs of diastolic dysfunction are found in about half of the cases, as LVH is present only in small percentage of these children.

    American heart journal 2006;151;3;725.e1-725.e9

  • Characteristics of the beta myosin heavy chain gene Ala26Val mutation in a Chinese family with hypertrophic cardiomyopathy.

    Liu SX, Hu SJ, Sun J, Wang J, Wang XT, Jiang Y and Cai J

    Department of Cardiovascular Medicine, The First Affiliated Hospital, College of Medical Science, Zhejiang University, QingChun Road 33, Hangzhou 310003, PR China. s0hu0001@hotmail.com

    Background: Genotype-phenotype studies have suggested that some mutations of genes encoding various components of the cardiac sarcomere cause hypertrophic cardiomyopathy (HCM) and are associated with the prognosis of patients with HCM. The aims of this study were to investigate the gene mutations of exons in the cardiac beta myosin heavy chain (MYH7) gene, the troponin T (TNNT2) gene, and the brain natriuretic peptide (BNP) gene, as well as to assess the effect of these mutations on the clinical features of Chinese patients with HCM.

    Methods: Five unrelated Chinese families with HCM were studied. Exons 3 and 18 in the MYH7 gene, exon 9 in the TNNT2 gene, and all three exons in the BNP gene were screened with the polymerase chain reaction (PCR) for genomic DNA amplification. Further study included purification of PCR products and direct sequencing of PCR fragments by fluorescent end labeling.

    Results: A C-to-T transition in codon 26 of exon 3 in the MYH7 gene was found in one family (including four patients and five carriers), resulting in an amino acid substitution of valine (Val) for alanine (Ala). The Ala26Val mutation was of incomplete dominance (penetrance 44%). This mutation was not seen in the other four families or in the control group. Moreover, the association between the gene mutations of exon 18 in MYH7, of exon 9 of TNNT2, and of all three exons in BNP and HCM was not found in the populations we studied.

    Conclusions: The missense mutation Ala26Val found in this one Chinese family was associated with a mild phenotype of HCM. The genetic and phenotypic heterogeneity of HCM exists in the Chinese population. It suggests that genetic and environmental factors may be involved in the pathogenesis of HCM.

    European journal of internal medicine 2005;16;5;328-33

  • A novel mutation in the PTPN11 gene in a patient with Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy.

    Takahashi K, Kogaki S, Kurotobi S, Nasuno S, Ohta M, Okabe H, Wada K, Sakai N, Taniike M and Ozono K

    Department of Developmental Medicine (Paediatrics), Osaka University Graduate School of Medicine, 2-2 Yamada-oka, 565-0871 Suita, Osaka, Japan.

    Unlabelled: A male infant with clinical features of Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy is reported. He manifested severe heart failure and failure to thrive. Administration of propranolol and cibenzoline improved ventricular outflow tract obstruction, leading to catch-up growth. Genetic analysis of the patient revealed a novel missense mutation in the PTPN11 gene.

    Conclusion: This is the first description of a patient with a Gln510Glu mutation in the protein-tyrosine phosphatase, non-receptor type 11 gene. This specific mutation may be associated with a rapidly progressive hypertrophic cardiomyopathy.

    European journal of pediatrics 2005;164;8;497-500

  • Prevalence of cardiac beta-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy.

    Perrot A, Schmidt-Traub H, Hoffmann B, Prager M, Bit-Avragim N, Rudenko RI, Usupbaeva DA, Kabaeva Z, Imanov B, Mirrakhimov MM, Dietz R, Wycisk A, Tendera M, Gessner R and Osterziel KJ

    Kardiologie am Campus Buch und Virchow-Klinikum, Charité-Universitätsmedizin Berlin und Max-Delbrück-Centrum für Molekulare Medizin, Wiltbergstrasse 50, 13125 Berlin, Germany. perrot@fvk-berlin.de

    Hypertrophic cardiomyopathy (HCM) is a frequent, autosomal-dominant cardiac disease and manifests predominantly as left ventricular hypertrophy. Mutations in the cardiac beta-myosin heavy chain gene (MYH7) are responsible for the disease in about 30% of cases where mutations were identified. We clinically evaluated a large group of 147 consecutive HCM patients from three cardiology centers in Germany, Poland, and Kyrgyzstan according to the same protocol. The DNA of the patients was systematically analyzed in the whole coding region of the MYH7 gene using PCR, single-strand conformation polymorphism analysis, and automated sequencing. Eleven different missense mutations (including seven novel ones) in 11 unrelated patients were identified, showing a mutation frequency of 7.5% in the study population. We further examined the families of five patients (three of German, one of Polish, and one of Kyrgyz origin) with 32 individuals in total. We observed a clear, age-dependent penetrance with onset of disease symptoms in the fourth decade of life. Genotype-phenotype correlations were different for each mutation, whereas the majority was associated with an intermediate/malign phenotype. In conclusion, we report a systematic molecular screening of the complete MYH7 gene in a large group of consecutive HCM patients, leading to a genetic diagnosis in 38 individuals. Information about the genotype in an individual from one family could be very useful for the clinician, especially when dealing with healthy relatives in doubt of their risk about developing HCM. The increasing application of genetic screening and the increasing knowledge about genotype-phenotype correlations will hopefully lead to an improved clinical management of HCM patients.

    Journal of molecular medicine (Berlin, Germany) 2005;83;6;468-77

  • High-throughput single-strand conformation polymorphism analysis on a microfabricated capillary array electrophoresis device.

    Tian H, Emrich CA, Scherer JR, Mathies RA, Andersen PS, Larsen LA and Christiansen M

    Department of Chemistry, University of California-Berkeley, Berkeley, CA 94720, USA.

    A high-density 384-lane microfabricated capillary array electrophoresis device is evaluated for high-throughput single-strand conformation polymorphism (SSCP) analysis. A delayed back bias direct electrokinetic injection scheme is used to provide better than 10-bp resolution with an 8.0-cm effective separation length. Separation of a HaeIII digest of PhiX174 yielded theoretical plate numbers of 4.0 x 10(6). Using 5% PDMA containing 10% glycerol and 15% urea, 21 single-nucleotide polymorphisms (SNPs) from HFE, MYL2, MYL3, and MYH7 genes associated with hereditary hemochromatosis (HHC) and hereditary hypertrophic cardiomyopathy (HCM) are discriminated at two running temperatures (25 degrees C and 40 degrees C), providing 100% sensitivity. The data in this study demonstrate that the 384-lane microCAE device provides the resolution and detection sensitivity required for SSCP analysis, showing its potential for ultrahigh-throughput mutation detection.

    Funded by: NHGRI NIH HHS: HG 01399

    Electrophoresis 2005;26;9;1834-42

  • Mutation screening in dilated cardiomyopathy: prominent role of the beta myosin heavy chain gene.

    Villard E, Duboscq-Bidot L, Charron P, Benaiche A, Conraads V, Sylvius N and Komajda M

    INSERM Unité 621, IFR14, CIB Pitié-Salpêtrière, 91 Bd de l'Hôpital, 75013 Paris, France. villard@chups.jussieu.fr

    Aims: Familial dilated cardiomyopathy (FDCM) is associated with mutations in more than 10 genes, but genes mutation frequencies and associated clinical features remain largely unknown. Here, we performed a mutation analysis of four genes involved in FDCM in a population of idiopathic DCM.

    A SSCP and sequencing mutation screening of all the exons coding for beta myosin heavy chain (MYH7 gene), cardiac T troponin (TNNT2 gene), phospholamban (PLN gene), and the cardio-specific exon of metavinculin (VCL gene) were performed in 96 independent patients (54 familial and 42 sporadic). It led to the identification of eight heterozygous mutations, seven new ones in MYH7, and the already described R141W mutation in TNNT2. MYH7 mutations (in five familial and two sporadic cases) substitute residues located either in the head (I201T, T412N, A550V) or tail domains (T1019N, R1193S, E1426K, R1634S) of the protein. DCM was not associated with skeletal myopathy or conduction defects in any patients. Contrasting clinical features were observed between MYH7 and TNNT2 mutations carriers. In MYH7 vs. TNNT2, mean age at diagnosis was late (P<0.03), penetrance was incomplete in adults (56 vs. 100%), and mean age at major cardiac event was higher (P<0.04).

    Conclusion: We have identified seven mutations in MYH7, one in TNNT2, and none in PLN or in the VCL cardio-specific exon. MYH7 appears as the most frequently mutated gene in our FDCM population (approximately 10%), and mutation carriers present with delayed onset, in contrast to TNNT2.

    European heart journal 2005;26;8;794-803

  • Sarcomeric genotyping in hypertrophic cardiomyopathy.

    Van Driest SL, Ommen SR, Tajik AJ, Gersh BJ and Ackerman MJ

    Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minn 55905, USA.

    Objective: To pool results from studies of patients with hypertrophic cardiomyopathy (HCM) to elucidate important phenotypic differences among genotypes.

    Data published from November 1998 through November 2004 were gathered and compared from unrelated study population genotyping studies from the Mayo Clinic (Rochester, Minn), Harvard Medical School (Boston, Mass), France, Germany, Sweden, Finland, and Spain. Standard statistical analysis techniques were used to pool and compare data across genotypes with respect to frequency of mutations, age at diagnosis, and degree of hypertrophy (left ventricular wall thickness).

    Results: The French study population harbored the highest frequency of mutations (61%), followed by the Mayo Clinic (38%), Harvard Medical School (36%), and Swedish (30%) study populations. For every study population, mutations in myosin binding protein C (MYBPC3) were the most common cause of HCM. Patients with a family history of HCM had mutations more frequently than those without. This pooled analysis revealed no statistically significant differences in left ventricular wall thickness or in mean age at diagnosis across all genotypes.

    Conclusions: Differentiation of sarcomeric genotypes, such as MYBPC3-HCM and MYH7-HCM, is not possible on the basis of currently reported phenotypic data. A myriad of genetic and/or environmental modifiers in addition to the primary disease-causing genetic substrate must play an important role in determining a patient's particular phenotype.

    Mayo Clinic proceedings 2005;80;4;463-9

  • The PTPN11 gene is not implicated in nonsyndromic hypertrophic cardiomyopathy.

    Roberts AE, Hult B, Rehm HL, Rehm HL, McDonough B, Barr S, Seidman CE, Seidman JG and Kucherlapati RS

    American journal of medical genetics. Part A 2005;132A;3;333-4

  • Mutations profile in Chinese patients with hypertrophic cardiomyopathy.

    Song L, Zou Y, Wang J, Wang Z, Zhen Y, Lou K, Zhang Q, Wang X, Wang H, Li J and Hui R

    Sino-German Laboratory for Molecular Medicine, Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.

    Background: There are more than 1 million patients with hypertrophic cardiomyopathy (HCM) in China, but the genetic basis is presently unknown.

    Methods: We investigated 100 independent patients with HCM (proband 51, sporadic 49) by sequencing the three most frequent HCM-causing genes (MYH7, MYBPC3, TNNT2).

    Results: Thirty-four patients (34%) carried 25 types of mutations in the selected genes, most (14/25) were newly identified. MYH7 and MYBPC3 accounted for 41% and 18% of the familial HCM, respectively. TNNT2 mutations only caused 2% of the familial HCM. These results suggested that MYH7 and MYBPC3 were the predominant genes responsible for HCM, and TNNT2 mutation less proportionally contributed to Chinese HCM. MYH7 mutations caused HCM at younger age, more frequent syncope and ECG abnormalities compared with MYBPC3 mutations. The patients carrying R663C, Q734P, E930K in MYH7 and R130C in TNNT2 expressed malignant phenotype. R403Q in MYH7, the most common hot and malignant mutation in Caucasians, was not identified in Chinese.

    Conclusion: We confirmed the diversity of mutation profile in different populations and suggest that a global registry of HCM mutations and their phenotypes is necessary to correlate genotype with phenotype.

    Clinica chimica acta; international journal of clinical chemistry 2005;351;1-2;209-16

  • [The role of mutation in cardiac beta-myosin heavy chain gene in population of patients].

    Seleznev DM, Gabrusenko SA, Parfenova EV, Naumov VG, Stambol'skiĭ DV and Tkachuk VA

    One of most widely spread causes of hypertrophic cardiomyopathy (HCMP) is mutation in cardiac beta-myosin heavy chain gene. Data on contribution of this mutation to development of HCMP in Russian patients are very limited. We conducted screening of beta-myosin heavy chain gene for the presence of mutations in 116 patients with confirmed HCMP (probands). DHPLC was used with subsequent sequencing of DNA fragments. Genetic defects of beta-myosin heavy chain were found more than in every 10-th patient. These defects were represented by 13 mutations (Ala729Pro mutation was found twice). Phenotypes of majority of known mutations in Russian population did not differ substantially from their phenotypes in other populations. Six mutations had not been previously described; most of them were associated with especially severe clinical and hemodynamic signs and relatively unfavorable course of the disease. Thus beta-myosin heavy chain gene mutation play important role in etiology of HCMP in patients in Russia.

    Kardiologiia 2005;45;4;15-20

  • [Mutations in beta myosin heavy chain gene: two mutations in Chinese with familial hypertrophic cardiomyopathy and the correlation between the genotype and phenotype].

    Xie WL, Liu WL, Hu DY, Cui W, Zhu TG, Li CL, Sun YH, Li L, Li TC, Bian H and Tong QG

    Department of Cardiology, Second Hospital, Peking University, Beijing 100044, China.

    Objective: To study the disease-causing gene mutation in Chinese with hypertrophic cardiomyopathy (HCM), and to analyze the correlation between the genotype and phenotype.

    Methods: Samples of peripheral blood were collected from five Chinese patients with HCM in whose families at least 2 HCM patients existed. The exon in the functional regions of the beta myosin heavy chain gene (beta-MHC) were amplified with PCR and the products were sequenced. The relation between the genotype and phenotype was analyzed.

    Results: Two mutations were first identified. Eighty controls were normal in the genetic test.

    Conclusion: beta-MHC may be the main disease-causing gene. Two mutations have different phenotypes. In one family, the identical mutation has different phenotypes and prognoses. The heterogeneity of phenotype suggests that multiple factors be involved in the pathogenesis.

    Zhonghua yi xue za zhi 2004;84;19;1610-3

  • Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy.

    Van Driest SL, Jaeger MA, Ommen SR, Will ML, Gersh BJ, Tajik AJ and Ackerman MJ

    Departments of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.

    Objectives: We sought to determine the prevalence and phenotype of beta-myosin heavy chain gene MYH7 mutations in a large cohort of unrelated patients with hypertrophic cardiomyopathy (HCM).

    Background: Hypertrophic cardiomyopathy is a heterogeneous cardiac disease. MYH7 mutations are one of the most common genetic causes of HCM and have been associated with severe hypertrophy, young age of diagnosis, and high risk of sudden cardiac death. However, these clinical findings from large, family studies have not been confirmed in a large unrelated cohort.

    Methods: Deoxyribonucleic (DNA) samples obtained from 389 HCM outpatients seen at this tertiary referral center were analyzed for mutations, using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing for all 38 protein-coding exons of MYH7. Clinical data were extracted from patient records blinded to patient genotype.

    Results: Fifty-eight patients (15%) harbored 40 different mutations in MYH7. Compared with HCM patients without MYH7 mutations, HCM patients with MYH7 were younger at diagnosis (32.9 vs. 42.7 years, p = 0.0002), had more hypertrophy (left ventricular wall thickness of 24.2 vs. 21.1 mm, p = 0.0009), and more frequently underwent myectomy (60% vs. 38%, p = 0.002). The HCM patients with MYH7 mutations more often had a family history of HCM (43% vs. 29%, p = 0.006), but there was no difference in family history of sudden death (16% vs. 14%, p = NS).

    Conclusions: In this setting, HCM patients with MYH7 were diagnosed at a younger age and had more hypertrophy, but they had no greater frequency of sudden death among first-degree relatives. Although these associations may prove useful for targeted gene screening, caution should be exercised in terms of using pathogenic status in risk stratification.

    Funded by: NICHD NIH HHS: HD42569

    Journal of the American College of Cardiology 2004;44;3;602-10

  • Human homozygous R403W mutant cardiac myosin presents disproportionate enhancement of mechanical and enzymatic properties.

    Keller DI, Coirault C, Rau T, Cheav T, Weyand M, Amann K, Lecarpentier Y, Richard P, Eschenhagen T and Carrier L

    INSERM U582, Institut de Myologie, Bâtiment Babinski, Groupe Hospitalier Pitié-Salpêtrière, 47, Bld de l'Hôpital, 75651 Paris cedex 13, France.

    Familial hypertrophic cardiomyopathy (FHC) is associated with mutations in 11 genes encoding sarcomeric proteins. Most families present mutations in MYBPC3 and MYH7 encoding cardiac myosin-binding protein C and beta-myosin heavy chain. The consequences of MYH7 mutations have been extensively studied at the molecular level, but controversial results have been obtained with either reduced or augmented myosin motor function depending on the type or homogeneity of myosin studied. In the present study, we took advantage of the accessibility to an explanted heart to analyze for the first time the properties of human homozygous mutant myosin. The patient exhibited eccentric hypertrophy with severely impaired ejection fraction leading to heart transplantation, and carries a homozygous mutation in MYH7 (R403W) and a heterozygous variant in MYBPC3 (V896M). In situ analysis of the left ventricular tissue showed myocyte disarray and hypertrophy plus interstitial fibrosis. In vitro motility assays showed a small, but significant increase in sliding velocity of fluorescent-labeled actin filaments over human mutant cardiac myosin-coated surface compared to control (+18%; P<0.001). Mutant myosin exhibited a large increase in maximal actin-activated ATPase activity (+114%; P<0.05) and Km for actin (+87%; P<0.05) when compared to control. These data show disproportionate enhancement of mechanical and enzymatic properties of human mutant myosin. This suggests inefficient ATP utilization and reduced mechanical efficiency in the myocardial tissue of the patient, which could play an important role in the development of FHC phenotype.

    Journal of molecular and cellular cardiology 2004;36;3;355-62

  • Familial aggregation of genetically heterogeneous hypertrophic cardiomyopathy: a boy with LEOPARD syndrome due to PTPN11 mutation and his nonsyndromic father lacking PTPN11 mutations.

    Digilio MC, Pacileo G, Sarkozy A, Limongelli G, Conti E, Cerrato F, Marino B, Pizzuti A, Calabrò R and Dallapiccola B

    Medical Genetics, Bambino Gesù Hospital, Rome, Italy. digilio@opbg.net

    Background: Nonsyndromic hypertrophic cardiomyopathy (HCM) is a primary cardiac disease transmitted as an autosomal dominant trait. Multiple chromosomal loci have been found to be involved in the etiology of this defect. LEOPARD syndrome is a genetic condition characteristically associated with HCM. Additional features of the syndrome include multiple lentigines, facial anomalies, sensorineural deafness, and growth retardation. Mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located at chromosome 12q24, have been identified in patients with LEOPARD syndrome.

    Cases: We report here on a patient with HCM presenting with classic clinical features of LEOPARD syndrome, whose father also has HCM, but lacks phenotypic anomalies of the syndrome. Molecular analysis searching for PTPN11 mutations was performed in this family. A missense mutation (836A-->G; Tyr279Cys) in exon 7 of PTPN11 gene was identified in the patient with LEOPARD syndrome, whereas no mutation in PTPN11 gene was detected in the father or in additional family members.

    Conclusions: Aggregation of syndromic and nonsyndromic HCM in the same family is an unusual pattern of recurrence. Although genetic heterogeneity of LEOPARD and nonsyndromic HCM is not disputed, the existence of peculiar interactions linking genes causing nonsyndromic HCM and HCM in LEOPARD syndrome can be hypothesized. Different genes can work together, and a more severe cardiac phenotype can be due to additive effects. The involvement of familial susceptibility to specific cardiac malformations based on the presence of common predisposing factors can also be considered. Further molecular studies may shed light on these observations.

    Birth defects research. Part A, Clinical and molecular teratology 2004;70;2;95-8

  • Detection of a new mutation in the beta-myosin heavy chain gene in an individual with hypertrophic cardiomyopathy.

    Marian AJ, Yu QT, Mares A, Hill R, Roberts R and Perryman MB

    Department of Medicine, Baylor College of Medicine, Houston, Texas 77030.

    Familial hypertrophic cardiomyopathy (FHCM) is an autosomal dominant disease affecting primarily the myocardium. The gene responsible for FHCM has been localized to chromosome 14 in some families and several mutations have been described in the beta-myosin heavy chain (beta MHC), a candidate gene for the disease. We recently identified a family with HCM in whom we did not detect any of the known mutations in the beta MHC gene (the alpha/beta MHC hybrid gene and the missense mutation in exons 13 and 9). However, we did observe a novel 9.5-kb BamHI restriction fragment length polymorphism detected by a beta MHC probe on Southern blots of DNA from the proband of this family. Similarly, a novel 3.8-kb TaqI polymorphism and a novel 4.3-kb HindIII polymorphism were detected on Southern blots of DNA from the same proband. Polymerase chain reaction (PCR) was used to amplify the segment of the beta MHC that was detected by pSC14 probe. PCR amplification of the distal 3'-end of the beta MHC gene yielded an additional product in the DNA template from the proband which was subsequently cloned and sequenced. The sequence analysis showed a 2.4-kb nucleotide deletion involving one allele of the beta MHC gene. The deletion includes part of the intron 39, exon 40 including the 3'-untranslated region and the polyadenylation signal, and part of the beta-alpha MHC intergenic region. This deletion was inherited in Mendelian fashion in an additional three members of this small family of which only the proband has developed clinically diagnosed HCM at a very late onset (age 59 yr), the other three family members are younger and have not developed the disease at the ages of 10, 32, and 33 yr.

    Funded by: NHLBI NIH HHS: P50-HL42267-01

    The Journal of clinical investigation 1992;90;6;2156-65

Literature (24)

Pubmed - human_disease

  • Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy.

    Osio A, Tan L, Chen SN, Lombardi R, Nagueh SF, Shete S, Roberts R, Willerson JT and Marian AJ

    Center for Cardiovascular Genetic Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Sciences Center, Houston, TX 77030, USA.

    Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in sarcomeric proteins (excluding phenocopy). The causal genes in approximately one-third of the cases remain unknown. We identified a family comprised of 6 clinically affected members. The phenotype was characterized by early onset of symptoms, pronounced cardiac hypertrophy, and cardiac arrhythmias. We excluded MYH7, MYBPC3, TNNT2, and ACTC1 as the causal gene either by direct sequencing or by haplotype analysis. To map the putative candidate sarcomeric gene, we perforbold locus-specific haplotyping to detect cosegregation of the locus haplotype with the phenotype, followed by mutation screening. We genotyped 5 short-tandem-repeat markers that spanned a 4.4-centimorgan region on 4q26-q27 locus and encompassed myozenin 2 (MYOZ2), a Z-disk protein. The maximum logarithm of odds score was 2.03 (P=0.005). All affected members shared a common haplotype, implicating MYOZ2 as the causal gene. To detect the causal mutation, we sequenced all exons and exon-intron boundaries of MYOZ2 in 10 family members and identified a T-->C missense mutation corresponding to S48P substitution, which cosegregated with inheritance of HCM (N=6). It was absent in 4 clinically normal family members and in 658 additional normal individuals. To determine frequency of the MYOZ2 mutations in HCM, we sequenced MYOZ2 in 516 HCM probands and detected another missense mutation (I246M). It was absent in 2 normal family members and 517 controls. Both mutations affect highly conserved amino acids. We conclude MYOZ2 is a novel causal gene for human HCM.

    Funded by: NHLBI NIH HHS: P50 HL054313, P50 HL054313-060012, P50 HL054313-070012, P50 HL054313-080012, P50 HL054313-08S10012, P50 HL054313-090012, P50 HL054313-100012, R01 HL068884, R01 HL068884-01, R01 HL068884-02, R01 HL068884-03, R01 HL068884-04, R01 HL068884-05, R01-HL68884

    Circulation research 2007;100;6;766-8

  • [Comparative study of gene mutation between Chinese patients with familial and sporadic hypertrophic cardiomyopathy].

    Pan GZ, Liu WL, Hu DY, Xie WL, Zhu TG, Li L, Li CL and Bian H

    Department of Cardiology, Fuxing Hospital Affiliated to Capital University of Medical Sciences, Beijing 100038, China.

    Objective: To compare the gene mutation between Chinese patients with familial and sporadic hypertrophic cardiomyopathy (HCM).

    Methods: Peripheral blood samples were collected from 36 patients with familial HCM (FHCM) and 50 patients with sporadic HCM (SHCM), all un-related and from different provinces of China. PCR was used to amplify the 26 protein-coding axons of beta-myosin heavy chain (MYH7), 16 exons for cardiac troponin T (TNNT2), and 38 exons for cardiac myosin-binding protein C (MYBPC3). The amplified products were sequenced and compared with the standard sequence in the genBank so as to determine the potential mutation sites.

    Results: (1) 13 of the 36 FHCM patients (36.1%) harbored 3 different mutations in MYH7 gene: Arg663His in exon18, Glu924Lys in exon 23, and Ile736Thr in exon 20. Of the 50 SHCM patients, only 1 (2%) harbored MYH7 gene missence mutation: Ile736Thr located in exon 20. (2) TNNT2 was not identified in all SHCM patients and FHCM patients. (3) MYBPC3 was not identified in all SHCM patients. Four FHCM patients harbored 2 different mutations: Arg502Trp in exon 18 and Arg346fs in exon 13 respectively.

    Conclusion: MYH7 and MYBPC3 may be the dominant disease-causing genes in Chinese familial HCM patients; however the mutation rate of MYH7 and MYBPC3 genes is significantly lower in the SHCM patients compared with the FHCM patients. TNNT2 seems not the predominant disease-causing gene in all Chinese patients with HCM.

    Zhonghua yi xue za zhi 2006;86;42;2998-3001

  • Mutation of Arg723Gly in beta-myosin heavy chain gene in five Chinese families with hypertrophic cardiomyopathy.

    Yang JH, Zheng DD, Dong NZ, Yang XJ, Song JP, Jiang TB, Cheng XJ, Li HX, Zhou BY, Zhao CM and Jiang WP

    Department of Cardiology, First Affiliated Hospital of Soochow University, Suzhou 215006, China. yangjhsz@163.com

    Background: Hypertrophic cardiomyopathy (HCM) is a form of cardiomyopathy with an autosomal dominant inherited disease, which is caused by mutations in at least one of the sarcomeric protein genes. Mutations in the beta-myosin heavy chain (beta-MHC) are the most common cause of HCM. This study was to reveal the disease-causing gene mutations in Chinese population with HCM, and to analyze the correlation between the genotype and phenotype.

    Methods: The exons 3 to 26 of MYH7 were amplified by PCR, and the PCR products were sequenced in five non-kin HCM patients. A 17-year-old patient was detected to be an Arg723Gly mutation carrier. Then his family was gene-screened, and the correlation between genotype and phenotype was analyzed.

    Results: The mutation of Arg723Gly in a Chinese family with HCM was detected for the first time. With a C-G transversion in nucleotide 13,619 of the MYH7 gene, located at the essential light chain interacting region in S1, the replacement of arginine by glycine took place at amino acid residue 723. A two-dimensional echocardiogram showed moderate asymmetrical septal hypertrophy with left atria enlargement. There was no obstruction in the left ventricular outflow tract. In his family, a total of 13 individuals were diagnosed HCM and 5 of them were dead of congestive heart failure at a mean age of 66-year-old. Eight living members were all detected to carry the mutation, in which 3 developed progressive heart failure. Moreover, the heart function of the people evidently deteriorates when their age are older than 50. The mutation and the disease show co-separated.

    Conclusion: The Arg723Gly mutation is a malignant type. In Chinese the mutation has the similar characters to the former report but has low degree malignant.

    Chinese medical journal 2006;119;21;1785-9

  • [Beta-myosin heavy-chain gene mutations in patients with hypertrophic cardiomyopathy].

    Laredo R, Monserrat L, Hermida-Prieto M, Fernández X, Rodríguez I, Cazón L, Alvariño I, Dumont C, Piñón P, Peteiro J, Bouzas B and Castro-Beiras A

    Servicio de Cardiología, Complejo Hospitalario Universitario Juan Canalejo e Instituto Universitario de Ciencias de la Salud de la Universidad de A Coruña, A Coruña, Spain.

    To determine the frequency of mutations in the beta-myosin heavy-chain gene (MYH7) in a cohort of patients with hypertrophic cardiomyopathy (HCM) and their families, and to investigate correlations between genotype and phenotype.

    Methods: Single-strand conformation polymorphism analysis and sequencing of fragments with abnormal MYH7 gene mobility were carried out in 128 consecutive index patients with HCM. The phenotypes of patients with and without mutations were compared and the phenotypes of identified families were recorded.

    Results: A total of 11 mutations were found in 13 families (10%); 7/11 had been previously described. The I736T mutation was found in three families and the A797T in two. One patient had two mutations (i.e., I736T and R787H). Mutations were more frequent in patients with a family history of sudden death (31%) and in those with severe hypertrophy (39% had a thickness > or = 30 mm). Mutations were found in 29 of 42 members of the 13 families, including six family members (20%) who were healthy carriers and aged < or = 36 years. Sudden death had occurred in eight members of four families: four in two families with the I736T mutation, one in a family with A797T, one in a family with R870H, and two in a family with A901P.

    Conclusions: MYH7 mutations were present in 10% of our families. Mutations were more frequent in patients with a family history of sudden death and in those with severe hypertrophy. Most mutations had been described previously. Some appeared in several families. For some mutations, the correlation between genotype and phenotype was stable, while for others, there were marked differences between the phenotypes of the index patients and their relatives, suggesting the presence of additional genetic factors that have yet to be identified.

    Revista espanola de cardiologia 2006;59;10;1008-18

  • A molecular screening strategy based on beta-myosin heavy chain, cardiac myosin binding protein C and troponin T genes in Italian patients with hypertrophic cardiomyopathy.

    Girolami F, Olivotto I, Passerini I, Zachara E, Nistri S, Re F, Fantini S, Baldini K, Torricelli F and Cecchi F

    Genetic Diagnostic Unit, Azienda Ospedaliero Universitaria Careggi, Florence, Italy. citogenbibl3@ao-careggi.toscana.it

    Background: Mutations causing hypertrophic cardiomyopathy (HCM) have been described in nine different genes of the sarcomere. Three genes account for most known mutations: beta-myosin heavy chain (MYH7), cardiac myosin binding protein C (MYBPC3) and cardiac troponin T (TNNT2). Their prevalence in Italian HCM patients is unknown. Thus, we prospectively assessed a molecular screening strategy of these three genes in a consecutive population with HCM from two Italian centres.

    Methods: Comprehensive screening of MYBPC3, MYH7 and TNNT2 was performed in 88 unrelated HCM patients by denaturing high-performance liquid chromatography and automatic sequencing.

    Results: We identified 32 mutations in 50 patients (57%); 16 were novel. The prevalence rates for MYBPC3, MYH7 and TNNT2 were 32%, 17% and 2%, respectively. MYBPC3 mutations were 18, including two frameshift, five splice-site and two nonsense. All were 'private' except insC1065 and R502Q, present in three and two patients, respectively. Moreover, E258K was found in 14% of patients, suggesting a founder effect. MYH7 mutations were 12, all missense; seven were novel. In TNNT2, only two mutations were found. In addition, five patients had a complex genotype [i.e. carried a double MYBPC3 mutation (n = 2), or were double heterozygous for mutations in MYBPC3 and MYH7 (n = 3)].

    Conclusions: The first comprehensive evaluation of MYBPC3, MYH7 and TNNT2 in an Italian HCM population allowed a genetic diagnosis in 57% of the patients. These data support a combined analysis of the three major sarcomeric genes as a rational and cost-effective initial approach to the molecular screening of HCM.

    Journal of cardiovascular medicine (Hagerstown, Md.) 2006;7;8;601-7

  • [Hypertrophic cardiomyopathy: infrequent mutation of the cardiac beta-myosin heavy-chain gene].

    Mora R, Merino JL, Peinado R, Olias F, García-Guereta L, del Cerro MJ, Tarín MN and Molano J

    Unidad de Genética Molecular, Servicio de Bioquímica, Hospital Universitario La Paz, Madrid, España.

    The aim of this study was to identify mutations in the cardiac heavy-chain beta-myosin gene (MYH7b) in a group of Spanish patients with hypertrophic cardiomyopathy. The study included 36 families with at least one member who had hypertrophic cardiomyopathy. DNA from exons 3 to 24 of the MYH7b gene was sequenced. Two mutations were identified: Arg858Cys and Met515Val. They occurred in two families, one of which was of Moroccan origin. This corresponds to a MYH7b gene mutation frequency of less than 5%. In contrast to findings in other Caucasian populations, MYH7b gene mutation occurred infrequently in this group of Spanish families with hypertrophic cardiomyopathy.

    Revista espanola de cardiologia 2006;59;8;846-9

  • Genotype-phenotype correlation of R870H mutation in hypertrophic cardiomyopathy.

    Tanjore RR, Sikindlapuram AD, Calambur N, Thakkar B, Kerkar PG and Nallari P

    Clinical genetics 2006;69;5;434-6

  • [Analysis of MYH7, MYBPC3 and TNNT2 gene mutations in 10 Chinese pedigrees with familial hypertrophic cardiomyopathy and the correlation between genotype and phenotype].

    Liu WL, Xie WL, Hu DY, Zhu TG, Li YT, Sun YH, Li CL, Li L, Li TC, Bian H, Tong QG, Yang SN, Fan RY and Cui W

    Cardiology Division, People's Hospital, Peking University, Beijing 100044, China.

    Objective: The aim of this study was to screen the disease-causing gene mutations and investigate the genotype-phenotype correlation in 10 Chinese pedigrees with familial hypertrophic cardiomyopathy (HCM).

    Methods: There are 91 family members from these 10 pedigrees and 5 members were normal mutated carriers, 23 members were HCM patients (14 male) aged from 1.5 to 73 years old. The functional regions of myosin heavy chain gene (MYH7), cardiac myosin-binding protein C (MYBPC3) and cardiac troponin T gene (TNNT2) were screened with PCR and direct sequencing technique. Clinical information from all patients was also evaluated in regard to the genotype.

    Results: Mutations were found in 5 out of 10 pedigrees. Mutations in MYH7 (Arg663His, Glu924Lys and Ile736Thr) were found in 3 pedigrees and 3 patients from these pedigrees suffered sudden death at age 20-48 years old during sport. Mutations in MYBPC3 were found in 2 pedigrees, 1 with complex mutation (Arg502Trp and splicing mutation IVS27 + 12C > T) and 1 with novel frame shift mutation (Gly347fs) and the latter pedigree has sudden death history. No mutation was identified in TNNT2.

    Conclusions: Although the Han Chinese is a relatively homogeneous ethnic group, different HCM gene mutations were responsible for familiar HCM suggesting the heterogeneity nature of the disease-causing genes and HCM MYH7 mutations are associated with a higher risk of sudden death in this cohort. Furthermore, identical mutation might result in different phenotypes suggesting that multiple factors might be involved in the pathogenesis of familiar HCM.

    Zhonghua xin xue guan bing za zhi 2006;34;3;202-7

  • Diastolic dysfunction without left ventricular hypertrophy is an early finding in children with hypertrophic cardiomyopathy-causing mutations in the beta-myosin heavy chain, alpha-tropomyosin, and myosin-binding protein C genes.

    Poutanen T, Tikanoja T, Jääskeläinen P, Jokinen E, Silvast A, Laakso M and Kuusisto J

    Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland. tuija.poutanen@koti.tpo.fi

    Objectives: We investigated the presence of left ventricular hypertrophy (LVH) and features of diastolic dysfunction in genotype-confirmed children from families with hypertrophic cardiomyopathy (HCM) and healthy control children.

    Background: In subjects with HCM-causing mutations, LVH usually does not evolve until adolescence. Diastolic dysfunction has not been systematically evaluated in children carrying HCM-causing mutations.

    Methods: All children (aged 1.5-16.7 years) from 14 HCM families with identified disease-causing mutations (the Arg719Trp mutation in the beta-myosin heavy chain gene [MYH7], the Asp175Asn mutation in the alpha-tropomyosin gene [TPM1], the Gln1061X mutation in the myosin-binding protein C gene [MYBPC3], and the IVS5-2A-->C mutation in the MYBPC3 gene) and 53 matched control children were examined with electrocardiography and 2- and 3-dimensional echocardiography (2DE and 3DE). Natriuretic peptides were measured in children from HCM families and 67 control children.

    Results: Of 53 children from HCM families, 27 (51%) had a disease-causing mutation (G+). G+ children had slightly thicker septum on 2DE compared with the control children (P = .004), but only 3 (11%) of 27 G+ children exceeded the 95th percentile values of the body surface area-adjusted maximal LV thickness of healthy children (the major echocardiographic criterion for HCM). However, prolonged isovolumetric relaxation time, increased left atrial volume on 3DE, or increased levels of NT-proANP, all features suggestive of diastolic dysfunction, were found in 14 (52%) of 27 G+ children.

    Conclusions: In children with HCM-causing mutations, signs of diastolic dysfunction are found in about half of the cases, as LVH is present only in small percentage of these children.

    American heart journal 2006;151;3;725.e1-725.e9

  • Characteristics of the beta myosin heavy chain gene Ala26Val mutation in a Chinese family with hypertrophic cardiomyopathy.

    Liu SX, Hu SJ, Sun J, Wang J, Wang XT, Jiang Y and Cai J

    Department of Cardiovascular Medicine, The First Affiliated Hospital, College of Medical Science, Zhejiang University, QingChun Road 33, Hangzhou 310003, PR China. s0hu0001@hotmail.com

    Background: Genotype-phenotype studies have suggested that some mutations of genes encoding various components of the cardiac sarcomere cause hypertrophic cardiomyopathy (HCM) and are associated with the prognosis of patients with HCM. The aims of this study were to investigate the gene mutations of exons in the cardiac beta myosin heavy chain (MYH7) gene, the troponin T (TNNT2) gene, and the brain natriuretic peptide (BNP) gene, as well as to assess the effect of these mutations on the clinical features of Chinese patients with HCM.

    Methods: Five unrelated Chinese families with HCM were studied. Exons 3 and 18 in the MYH7 gene, exon 9 in the TNNT2 gene, and all three exons in the BNP gene were screened with the polymerase chain reaction (PCR) for genomic DNA amplification. Further study included purification of PCR products and direct sequencing of PCR fragments by fluorescent end labeling.

    Results: A C-to-T transition in codon 26 of exon 3 in the MYH7 gene was found in one family (including four patients and five carriers), resulting in an amino acid substitution of valine (Val) for alanine (Ala). The Ala26Val mutation was of incomplete dominance (penetrance 44%). This mutation was not seen in the other four families or in the control group. Moreover, the association between the gene mutations of exon 18 in MYH7, of exon 9 of TNNT2, and of all three exons in BNP and HCM was not found in the populations we studied.

    Conclusions: The missense mutation Ala26Val found in this one Chinese family was associated with a mild phenotype of HCM. The genetic and phenotypic heterogeneity of HCM exists in the Chinese population. It suggests that genetic and environmental factors may be involved in the pathogenesis of HCM.

    European journal of internal medicine 2005;16;5;328-33

  • A novel mutation in the PTPN11 gene in a patient with Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy.

    Takahashi K, Kogaki S, Kurotobi S, Nasuno S, Ohta M, Okabe H, Wada K, Sakai N, Taniike M and Ozono K

    Department of Developmental Medicine (Paediatrics), Osaka University Graduate School of Medicine, 2-2 Yamada-oka, 565-0871 Suita, Osaka, Japan.

    Unlabelled: A male infant with clinical features of Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy is reported. He manifested severe heart failure and failure to thrive. Administration of propranolol and cibenzoline improved ventricular outflow tract obstruction, leading to catch-up growth. Genetic analysis of the patient revealed a novel missense mutation in the PTPN11 gene.

    Conclusion: This is the first description of a patient with a Gln510Glu mutation in the protein-tyrosine phosphatase, non-receptor type 11 gene. This specific mutation may be associated with a rapidly progressive hypertrophic cardiomyopathy.

    European journal of pediatrics 2005;164;8;497-500

  • Prevalence of cardiac beta-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy.

    Perrot A, Schmidt-Traub H, Hoffmann B, Prager M, Bit-Avragim N, Rudenko RI, Usupbaeva DA, Kabaeva Z, Imanov B, Mirrakhimov MM, Dietz R, Wycisk A, Tendera M, Gessner R and Osterziel KJ

    Kardiologie am Campus Buch und Virchow-Klinikum, Charité-Universitätsmedizin Berlin und Max-Delbrück-Centrum für Molekulare Medizin, Wiltbergstrasse 50, 13125 Berlin, Germany. perrot@fvk-berlin.de

    Hypertrophic cardiomyopathy (HCM) is a frequent, autosomal-dominant cardiac disease and manifests predominantly as left ventricular hypertrophy. Mutations in the cardiac beta-myosin heavy chain gene (MYH7) are responsible for the disease in about 30% of cases where mutations were identified. We clinically evaluated a large group of 147 consecutive HCM patients from three cardiology centers in Germany, Poland, and Kyrgyzstan according to the same protocol. The DNA of the patients was systematically analyzed in the whole coding region of the MYH7 gene using PCR, single-strand conformation polymorphism analysis, and automated sequencing. Eleven different missense mutations (including seven novel ones) in 11 unrelated patients were identified, showing a mutation frequency of 7.5% in the study population. We further examined the families of five patients (three of German, one of Polish, and one of Kyrgyz origin) with 32 individuals in total. We observed a clear, age-dependent penetrance with onset of disease symptoms in the fourth decade of life. Genotype-phenotype correlations were different for each mutation, whereas the majority was associated with an intermediate/malign phenotype. In conclusion, we report a systematic molecular screening of the complete MYH7 gene in a large group of consecutive HCM patients, leading to a genetic diagnosis in 38 individuals. Information about the genotype in an individual from one family could be very useful for the clinician, especially when dealing with healthy relatives in doubt of their risk about developing HCM. The increasing application of genetic screening and the increasing knowledge about genotype-phenotype correlations will hopefully lead to an improved clinical management of HCM patients.

    Journal of molecular medicine (Berlin, Germany) 2005;83;6;468-77

  • High-throughput single-strand conformation polymorphism analysis on a microfabricated capillary array electrophoresis device.

    Tian H, Emrich CA, Scherer JR, Mathies RA, Andersen PS, Larsen LA and Christiansen M

    Department of Chemistry, University of California-Berkeley, Berkeley, CA 94720, USA.

    A high-density 384-lane microfabricated capillary array electrophoresis device is evaluated for high-throughput single-strand conformation polymorphism (SSCP) analysis. A delayed back bias direct electrokinetic injection scheme is used to provide better than 10-bp resolution with an 8.0-cm effective separation length. Separation of a HaeIII digest of PhiX174 yielded theoretical plate numbers of 4.0 x 10(6). Using 5% PDMA containing 10% glycerol and 15% urea, 21 single-nucleotide polymorphisms (SNPs) from HFE, MYL2, MYL3, and MYH7 genes associated with hereditary hemochromatosis (HHC) and hereditary hypertrophic cardiomyopathy (HCM) are discriminated at two running temperatures (25 degrees C and 40 degrees C), providing 100% sensitivity. The data in this study demonstrate that the 384-lane microCAE device provides the resolution and detection sensitivity required for SSCP analysis, showing its potential for ultrahigh-throughput mutation detection.

    Funded by: NHGRI NIH HHS: HG 01399

    Electrophoresis 2005;26;9;1834-42

  • Mutation screening in dilated cardiomyopathy: prominent role of the beta myosin heavy chain gene.

    Villard E, Duboscq-Bidot L, Charron P, Benaiche A, Conraads V, Sylvius N and Komajda M

    INSERM Unité 621, IFR14, CIB Pitié-Salpêtrière, 91 Bd de l'Hôpital, 75013 Paris, France. villard@chups.jussieu.fr

    Aims: Familial dilated cardiomyopathy (FDCM) is associated with mutations in more than 10 genes, but genes mutation frequencies and associated clinical features remain largely unknown. Here, we performed a mutation analysis of four genes involved in FDCM in a population of idiopathic DCM.

    A SSCP and sequencing mutation screening of all the exons coding for beta myosin heavy chain (MYH7 gene), cardiac T troponin (TNNT2 gene), phospholamban (PLN gene), and the cardio-specific exon of metavinculin (VCL gene) were performed in 96 independent patients (54 familial and 42 sporadic). It led to the identification of eight heterozygous mutations, seven new ones in MYH7, and the already described R141W mutation in TNNT2. MYH7 mutations (in five familial and two sporadic cases) substitute residues located either in the head (I201T, T412N, A550V) or tail domains (T1019N, R1193S, E1426K, R1634S) of the protein. DCM was not associated with skeletal myopathy or conduction defects in any patients. Contrasting clinical features were observed between MYH7 and TNNT2 mutations carriers. In MYH7 vs. TNNT2, mean age at diagnosis was late (P<0.03), penetrance was incomplete in adults (56 vs. 100%), and mean age at major cardiac event was higher (P<0.04).

    Conclusion: We have identified seven mutations in MYH7, one in TNNT2, and none in PLN or in the VCL cardio-specific exon. MYH7 appears as the most frequently mutated gene in our FDCM population (approximately 10%), and mutation carriers present with delayed onset, in contrast to TNNT2.

    European heart journal 2005;26;8;794-803

  • Sarcomeric genotyping in hypertrophic cardiomyopathy.

    Van Driest SL, Ommen SR, Tajik AJ, Gersh BJ and Ackerman MJ

    Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minn 55905, USA.

    Objective: To pool results from studies of patients with hypertrophic cardiomyopathy (HCM) to elucidate important phenotypic differences among genotypes.

    Data published from November 1998 through November 2004 were gathered and compared from unrelated study population genotyping studies from the Mayo Clinic (Rochester, Minn), Harvard Medical School (Boston, Mass), France, Germany, Sweden, Finland, and Spain. Standard statistical analysis techniques were used to pool and compare data across genotypes with respect to frequency of mutations, age at diagnosis, and degree of hypertrophy (left ventricular wall thickness).

    Results: The French study population harbored the highest frequency of mutations (61%), followed by the Mayo Clinic (38%), Harvard Medical School (36%), and Swedish (30%) study populations. For every study population, mutations in myosin binding protein C (MYBPC3) were the most common cause of HCM. Patients with a family history of HCM had mutations more frequently than those without. This pooled analysis revealed no statistically significant differences in left ventricular wall thickness or in mean age at diagnosis across all genotypes.

    Conclusions: Differentiation of sarcomeric genotypes, such as MYBPC3-HCM and MYH7-HCM, is not possible on the basis of currently reported phenotypic data. A myriad of genetic and/or environmental modifiers in addition to the primary disease-causing genetic substrate must play an important role in determining a patient's particular phenotype.

    Mayo Clinic proceedings 2005;80;4;463-9

  • The PTPN11 gene is not implicated in nonsyndromic hypertrophic cardiomyopathy.

    Roberts AE, Hult B, Rehm HL, Rehm HL, McDonough B, Barr S, Seidman CE, Seidman JG and Kucherlapati RS

    American journal of medical genetics. Part A 2005;132A;3;333-4

  • Mutations profile in Chinese patients with hypertrophic cardiomyopathy.

    Song L, Zou Y, Wang J, Wang Z, Zhen Y, Lou K, Zhang Q, Wang X, Wang H, Li J and Hui R

    Sino-German Laboratory for Molecular Medicine, Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.

    Background: There are more than 1 million patients with hypertrophic cardiomyopathy (HCM) in China, but the genetic basis is presently unknown.

    Methods: We investigated 100 independent patients with HCM (proband 51, sporadic 49) by sequencing the three most frequent HCM-causing genes (MYH7, MYBPC3, TNNT2).

    Results: Thirty-four patients (34%) carried 25 types of mutations in the selected genes, most (14/25) were newly identified. MYH7 and MYBPC3 accounted for 41% and 18% of the familial HCM, respectively. TNNT2 mutations only caused 2% of the familial HCM. These results suggested that MYH7 and MYBPC3 were the predominant genes responsible for HCM, and TNNT2 mutation less proportionally contributed to Chinese HCM. MYH7 mutations caused HCM at younger age, more frequent syncope and ECG abnormalities compared with MYBPC3 mutations. The patients carrying R663C, Q734P, E930K in MYH7 and R130C in TNNT2 expressed malignant phenotype. R403Q in MYH7, the most common hot and malignant mutation in Caucasians, was not identified in Chinese.

    Conclusion: We confirmed the diversity of mutation profile in different populations and suggest that a global registry of HCM mutations and their phenotypes is necessary to correlate genotype with phenotype.

    Clinica chimica acta; international journal of clinical chemistry 2005;351;1-2;209-16

  • [The role of mutation in cardiac beta-myosin heavy chain gene in population of patients].

    Seleznev DM, Gabrusenko SA, Parfenova EV, Naumov VG, Stambol'skiĭ DV and Tkachuk VA

    One of most widely spread causes of hypertrophic cardiomyopathy (HCMP) is mutation in cardiac beta-myosin heavy chain gene. Data on contribution of this mutation to development of HCMP in Russian patients are very limited. We conducted screening of beta-myosin heavy chain gene for the presence of mutations in 116 patients with confirmed HCMP (probands). DHPLC was used with subsequent sequencing of DNA fragments. Genetic defects of beta-myosin heavy chain were found more than in every 10-th patient. These defects were represented by 13 mutations (Ala729Pro mutation was found twice). Phenotypes of majority of known mutations in Russian population did not differ substantially from their phenotypes in other populations. Six mutations had not been previously described; most of them were associated with especially severe clinical and hemodynamic signs and relatively unfavorable course of the disease. Thus beta-myosin heavy chain gene mutation play important role in etiology of HCMP in patients in Russia.

    Kardiologiia 2005;45;4;15-20

  • [Mutations in beta myosin heavy chain gene: two mutations in Chinese with familial hypertrophic cardiomyopathy and the correlation between the genotype and phenotype].

    Xie WL, Liu WL, Hu DY, Cui W, Zhu TG, Li CL, Sun YH, Li L, Li TC, Bian H and Tong QG

    Department of Cardiology, Second Hospital, Peking University, Beijing 100044, China.

    Objective: To study the disease-causing gene mutation in Chinese with hypertrophic cardiomyopathy (HCM), and to analyze the correlation between the genotype and phenotype.

    Methods: Samples of peripheral blood were collected from five Chinese patients with HCM in whose families at least 2 HCM patients existed. The exon in the functional regions of the beta myosin heavy chain gene (beta-MHC) were amplified with PCR and the products were sequenced. The relation between the genotype and phenotype was analyzed.

    Results: Two mutations were first identified. Eighty controls were normal in the genetic test.

    Conclusion: beta-MHC may be the main disease-causing gene. Two mutations have different phenotypes. In one family, the identical mutation has different phenotypes and prognoses. The heterogeneity of phenotype suggests that multiple factors be involved in the pathogenesis.

    Zhonghua yi xue za zhi 2004;84;19;1610-3

  • Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy.

    Van Driest SL, Jaeger MA, Ommen SR, Will ML, Gersh BJ, Tajik AJ and Ackerman MJ

    Departments of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.

    Objectives: We sought to determine the prevalence and phenotype of beta-myosin heavy chain gene MYH7 mutations in a large cohort of unrelated patients with hypertrophic cardiomyopathy (HCM).

    Background: Hypertrophic cardiomyopathy is a heterogeneous cardiac disease. MYH7 mutations are one of the most common genetic causes of HCM and have been associated with severe hypertrophy, young age of diagnosis, and high risk of sudden cardiac death. However, these clinical findings from large, family studies have not been confirmed in a large unrelated cohort.

    Methods: Deoxyribonucleic (DNA) samples obtained from 389 HCM outpatients seen at this tertiary referral center were analyzed for mutations, using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing for all 38 protein-coding exons of MYH7. Clinical data were extracted from patient records blinded to patient genotype.

    Results: Fifty-eight patients (15%) harbored 40 different mutations in MYH7. Compared with HCM patients without MYH7 mutations, HCM patients with MYH7 were younger at diagnosis (32.9 vs. 42.7 years, p = 0.0002), had more hypertrophy (left ventricular wall thickness of 24.2 vs. 21.1 mm, p = 0.0009), and more frequently underwent myectomy (60% vs. 38%, p = 0.002). The HCM patients with MYH7 mutations more often had a family history of HCM (43% vs. 29%, p = 0.006), but there was no difference in family history of sudden death (16% vs. 14%, p = NS).

    Conclusions: In this setting, HCM patients with MYH7 were diagnosed at a younger age and had more hypertrophy, but they had no greater frequency of sudden death among first-degree relatives. Although these associations may prove useful for targeted gene screening, caution should be exercised in terms of using pathogenic status in risk stratification.

    Funded by: NICHD NIH HHS: HD42569

    Journal of the American College of Cardiology 2004;44;3;602-10

  • Human homozygous R403W mutant cardiac myosin presents disproportionate enhancement of mechanical and enzymatic properties.

    Keller DI, Coirault C, Rau T, Cheav T, Weyand M, Amann K, Lecarpentier Y, Richard P, Eschenhagen T and Carrier L

    INSERM U582, Institut de Myologie, Bâtiment Babinski, Groupe Hospitalier Pitié-Salpêtrière, 47, Bld de l'Hôpital, 75651 Paris cedex 13, France.

    Familial hypertrophic cardiomyopathy (FHC) is associated with mutations in 11 genes encoding sarcomeric proteins. Most families present mutations in MYBPC3 and MYH7 encoding cardiac myosin-binding protein C and beta-myosin heavy chain. The consequences of MYH7 mutations have been extensively studied at the molecular level, but controversial results have been obtained with either reduced or augmented myosin motor function depending on the type or homogeneity of myosin studied. In the present study, we took advantage of the accessibility to an explanted heart to analyze for the first time the properties of human homozygous mutant myosin. The patient exhibited eccentric hypertrophy with severely impaired ejection fraction leading to heart transplantation, and carries a homozygous mutation in MYH7 (R403W) and a heterozygous variant in MYBPC3 (V896M). In situ analysis of the left ventricular tissue showed myocyte disarray and hypertrophy plus interstitial fibrosis. In vitro motility assays showed a small, but significant increase in sliding velocity of fluorescent-labeled actin filaments over human mutant cardiac myosin-coated surface compared to control (+18%; P<0.001). Mutant myosin exhibited a large increase in maximal actin-activated ATPase activity (+114%; P<0.05) and Km for actin (+87%; P<0.05) when compared to control. These data show disproportionate enhancement of mechanical and enzymatic properties of human mutant myosin. This suggests inefficient ATP utilization and reduced mechanical efficiency in the myocardial tissue of the patient, which could play an important role in the development of FHC phenotype.

    Journal of molecular and cellular cardiology 2004;36;3;355-62

  • Detection of a new mutation in the beta-myosin heavy chain gene in an individual with hypertrophic cardiomyopathy.

    Marian AJ, Yu QT, Mares A, Hill R, Roberts R and Perryman MB

    Department of Medicine, Baylor College of Medicine, Houston, Texas 77030.

    Familial hypertrophic cardiomyopathy (FHCM) is an autosomal dominant disease affecting primarily the myocardium. The gene responsible for FHCM has been localized to chromosome 14 in some families and several mutations have been described in the beta-myosin heavy chain (beta MHC), a candidate gene for the disease. We recently identified a family with HCM in whom we did not detect any of the known mutations in the beta MHC gene (the alpha/beta MHC hybrid gene and the missense mutation in exons 13 and 9). However, we did observe a novel 9.5-kb BamHI restriction fragment length polymorphism detected by a beta MHC probe on Southern blots of DNA from the proband of this family. Similarly, a novel 3.8-kb TaqI polymorphism and a novel 4.3-kb HindIII polymorphism were detected on Southern blots of DNA from the same proband. Polymerase chain reaction (PCR) was used to amplify the segment of the beta MHC that was detected by pSC14 probe. PCR amplification of the distal 3'-end of the beta MHC gene yielded an additional product in the DNA template from the proband which was subsequently cloned and sequenced. The sequence analysis showed a 2.4-kb nucleotide deletion involving one allele of the beta MHC gene. The deletion includes part of the intron 39, exon 40 including the 3'-untranslated region and the polyadenylation signal, and part of the beta-alpha MHC intergenic region. This deletion was inherited in Mendelian fashion in an additional three members of this small family of which only the proband has developed clinically diagnosed HCM at a very late onset (age 59 yr), the other three family members are younger and have not developed the disease at the ages of 10, 32, and 33 yr.

    Funded by: NHLBI NIH HHS: P50-HL42267-01

    The Journal of clinical investigation 1992;90;6;2156-65

Pubmed - other

  • Mutation screening of the PTPN11 gene in hypertrophic cardiomyopathy.

    Limongelli G, Hawkes L, Calabro R, McKenna WJ and Syrris P

    Department of Medicine, University College London and University College London Hospitals Trust, Cobbold Laboratories, 7th Floor, Jules Thorn Institute, Middlesex Hospital, 48 Riding House Street, London W1W 7EY, UK.

    Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease and a major cause of sudden death. It is an autosomal dominant disorder predominantly caused by mutations in genes encoding for sarcomeric proteins. Only 50-60% of HCM probands have mutations in known genes suggesting the presence of additional disease genes. Noonan and LEOPARD syndromes are characterised by multiple dysmorphia and cardiac defects with HCM present in approximately 20% of cases. Both syndromes are caused by mutations in the PTPN11 gene which codes for the protein tyrosine phosphatase SHP-2. It is suspected but unproven that the cardiac phenotype may predominate or even be present in isolation. In order to determine possible involvement of this gene in the pathogenesis of HCM, we performed mutation screening of the PTPN11 coding region in 250 selected HCM probands (200 patients without mutations in sarcomeric genes and 50 with identified mutations). No mutations in PTPN11 were identified. Our data suggests that mutations in the PTPN11 gene are not a cause of HCM in the absence of Noonan/LEOPARD syndromes.

    European journal of medical genetics 2006;49;5;426-30

  • Familial aggregation of genetically heterogeneous hypertrophic cardiomyopathy: a boy with LEOPARD syndrome due to PTPN11 mutation and his nonsyndromic father lacking PTPN11 mutations.

    Digilio MC, Pacileo G, Sarkozy A, Limongelli G, Conti E, Cerrato F, Marino B, Pizzuti A, Calabrò R and Dallapiccola B

    Medical Genetics, Bambino Gesù Hospital, Rome, Italy. digilio@opbg.net

    Background: Nonsyndromic hypertrophic cardiomyopathy (HCM) is a primary cardiac disease transmitted as an autosomal dominant trait. Multiple chromosomal loci have been found to be involved in the etiology of this defect. LEOPARD syndrome is a genetic condition characteristically associated with HCM. Additional features of the syndrome include multiple lentigines, facial anomalies, sensorineural deafness, and growth retardation. Mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located at chromosome 12q24, have been identified in patients with LEOPARD syndrome.

    Cases: We report here on a patient with HCM presenting with classic clinical features of LEOPARD syndrome, whose father also has HCM, but lacks phenotypic anomalies of the syndrome. Molecular analysis searching for PTPN11 mutations was performed in this family. A missense mutation (836A-->G; Tyr279Cys) in exon 7 of PTPN11 gene was identified in the patient with LEOPARD syndrome, whereas no mutation in PTPN11 gene was detected in the father or in additional family members.

    Conclusions: Aggregation of syndromic and nonsyndromic HCM in the same family is an unusual pattern of recurrence. Although genetic heterogeneity of LEOPARD and nonsyndromic HCM is not disputed, the existence of peculiar interactions linking genes causing nonsyndromic HCM and HCM in LEOPARD syndrome can be hypothesized. Different genes can work together, and a more severe cardiac phenotype can be due to additive effects. The involvement of familial susceptibility to specific cardiac malformations based on the presence of common predisposing factors can also be considered. Further molecular studies may shed light on these observations.

    Birth defects research. Part A, Clinical and molecular teratology 2004;70;2;95-8

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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