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In Maine Coon (MC) cats the c.91G > C mutation in the gene MYBPC3, coding for cardiac myosin binding protein C (cMyBP-C), is associated with feline hypertrophic cardiomyopathy (fHCM). The mutation causes a substitution of an alanine for a proline at residue 31 (p.A31P) of cMyBP-C. The pattern of inheritance has been considered autosomal dominant based on a single pedigree. However, larger studies are needed to establish the significance of cats being heterozygous or homozygous for the mutation with respect to echocardiographic indices and the probability of developing fHCM. The objective of the present study was to establish the clinical significance of being homozygous or heterozygous for the p.A31P cMyBP-C mutation in young to middle-aged cats. The cohort consisted of 332 MC cats, 282 cats < 4 years (85%). All cats were examined by 2-D and M-mode echocardiography. DNA was extracted from blood samples or buccal swabs and screened for the p.A31P cMyBP-C mutation in exon 3 of the gene, using polymerase chain reaction followed by DNA sequencing. The fHCM prevalence was 6.3% in the cohort. Eighteen cats were homozygous and 89 cats were heterozygous for the mutation. The odds ratio for having fHCM for homozygous cats was 21.6 (95% confidence interval 7.01-66.2) - when the group of equivocal cats was categorized as non-affected. Overall, 50% of the cats that were homozygous for the mutation had fHCM. p.A31P heterozygosity was not associated with a significant odds ratio for fHCM. In cats in the 4 to 6 years of age range a similar, non significant, odds ratio was seen in heterozygous cats. Only two cats over four years were homozygous and both were diagnosed with fHCM. As there is no significant odds ratio associated with being heterozygous for the pA31P cMyBP-C mutation at this age, the mutation must have a very low penetrance in this group. From our data it would appear that most MC cats that develop fHCM due to the p.A31P mutation prior to the age of approximately 6 years do so because they are homozygous for this mutation. Show less

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Fourteen sarcomeric and sarcomere-related genes have been implicated in HCM etiology, those encoding β-myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3) reported as the most frequently mutated: in fact, these account for around 50% of all cases related to sarcomeric gene mutations, which are collectively responsible for approximately 70% of all HCM cases. Here, we used denaturing high-performance liquid chromatography followed by bidirectional sequencing to screen the coding regions of MYH7 and MYBPC3 in a cohort (n = 125) of Italian patients presenting with HCM. We found 6 MHY7 mutations in 9/125 patients and 18 MYBPC3 mutations in 19/125 patients. Of the three novel MYH7 mutations found, two were missense, and one was a silent mutation; of the eight novel MYBPC3 mutations, one was a substitution, three were stop codons, and four were missense mutations. Thus, our cohort of Italian HCM patients did not harbor the high frequency of mutations usually found in MYH7 and MYBPC3. This finding, coupled to the clinical diversity of our cohort, emphasizes the complexity of HCM and the need for more inclusive investigative approaches in order to fully understand the pathogenesis of this disease. Show less

The aim of this study was to describe the clinical profile associated with triple sarcomere gene mutations in a large hypertrophic cardiomyopathy (HCM) cohort. In patients with HCM, double or compound sarcomere gene mutation heterozygosity might be associated with earlier disease onset and more severe outcome. The occurrence of triple mutations has not been reported. A total of 488 unrelated index HCM patients underwent screening for myofilament gene mutations by direct deoxyribonucleic acid sequencing of 8 genes, including myosin binding protein C (MYBPC3), beta-myosin heavy chain (MYH7), regulatory and essential light chains (MYL2, MYL3), troponin-T (TNNT2), troponin-I (TNNI3), alpha-tropomyosin (TPM1), and actin (ACTC). Of the 488 index patients, 4 (0.8%) harbored triple mutations, as follows: MYH7-R869H, MYBPC3-E258K, and TNNI3-A86fs in a 32-year-old woman; MYH7-R723C, MYH7-E1455X, and MYBPC3-E165D in a 46-year old man; MYH7-R869H, MYBPC3-K1065fs, and MYBPC3-P371R in a 45-year old woman; and MYH7-R1079Q, MYBPC3-Q969X, and MYBPC3-R668H in a 50-year old woman. One had a history of resuscitated cardiac arrest, and 3 had significant risk factors for sudden cardiac death, prompting the insertion of an implantable cardioverter-defibrillator in all, with appropriate shocks in 2 patients. Moreover, 3 of 4 patients had a severe phenotype with progression to end-stage HCM by the fourth decade, requiring cardiac transplantation (n=1) or biventricular pacing (n=2). The fourth patient, however, had clinically mild disease. Hypertrophic cardiomyopathy caused by triple sarcomere gene mutations was rare but conferred a remarkably increased risk of end-stage progression and ventricular arrhythmias, supporting an association between multiple sarcomere defects and adverse outcome. Comprehensive genetic testing might provide important insights to risk stratification and potentially indicate the need for differential surveillance strategies based on genotype. Show less

Mutations in the cardiac myosin-binding protein C gene (MYBPC3) have been reported to be associated with delayed expression of hypertrophic cardiomyopathy (HCM) and a relatively good prognosis. The aim of this study was to evaluate clinical manifestations in patients with familial HCM caused by a novel nonsense mutation, S297X, in MYBPC3. We analyzed the sarcomere protein genes in 93 probands with HCM. The nonsense mutation S297X in MYBPC3 was present in nine subjects from two unrelated families. Eight of those nine subjects with this mutation were found to be phenotype-positive and the remaining individual was not affected phenotypically. The age range at diagnosis was 9-75 years. There was no family history of sudden death in either family. At presentation, there were various left ventricular hypertrophy (LVH) patterns, including Maron type III hypertrophy from the LV base to apex, hypertrophy confined to the anterolateral wall at the basal LV wall. Two patients showed a significant LV outflow tract gradient and one patient showed intra-right-ventricular obstruction. During follow-up, one patient was repeatedly hospitalized for the treatment of heart failure after development of paroxysmal atrial fibrillation at the age of 86 years and the remaining eight subjects were in relatively stable condition and did not require hospitalization for the treatment of HCM-related events. The novel mutation S297X in MYBPC3 causes HCM in a broad range of ages and heterogeneous clinical manifestations, though the clinical course in patients with this mutation seems to be benign. Show less

Rare variants in >30 genes have been shown to cause idiopathic or familial dilated cardiomyopathy (DCM), but the frequency of genetic causation remains poorly understood. We have previously resequenced 9 genes in a cohort of idiopathic or familial DCM probands for rare variants, and now we report resequencing results for 5 more genes with established relationships to DCM. Blood samples were collected, and DNA specimens were prepared from 312 patients, 181 with familial DCM and 131 with idiopathic DCM. Genomic DNA underwent bidirectional sequencing, and DNA of additional family members underwent analysis when a rare variant was identified. We identified rare variants in 34 probands (10.9% overall), including 29 unique protein-altering rare variants and 2 splicing variants that were absent in 246 control subjects (492 chromosomes). These variants were 12 MYBPC3 (myosin-binding protein C) in 13 (4.2%) probands, 8 MYH6 (alpha-myosin heavy chain) in 10 (3.2%), 6 TPM1 (tropomyosin) in 6 (1.9%), 4 TNNC1 (cardiac troponin C) in 4 (1.3%), and 1 TNNI3 (cardiac troponin I) in 2 (0.6%). Variants were classified as likely or possibly disease causing in 13 and 20 probands, respectively (n=33; 10.6% overall). One MYH6 variant was classified as unlikely to be disease causing. Rare variants in these 5 genes likely or possibly caused 10.6% of DCM in this cohort. When combined with our prior resequencing reports, approximately 27% of DCM probands had possible or likely disease-causing variants identified. Show less

We sought to describe the long-term outcome of individuals in 4 Korean families with hypertrophic cardiomyopathy (HCM) with known mutations. Long-term clinical features of familial HCM might be characterized according to the mutation causing HCM. We performed long-term (mean, 13.1 y) clinical evaluations on 46 subjects from 4 Korean families with different mutations. Myosin light chain 3 gene (MYL3) mutation was associated with late-onset HCM with relatively poor prognosis; 1 sudden cardiac death and 2 cases of heart failure with atrial fibrillation occurred among 12 subjects with this mutation. Myosin binding protein C gene (MYBPC3) mutation was associated with 2 cases of sudden cardiac death and 3 cases of heart failure among 7 affected members. Cardiac troponin I type 3 gene (TNNI3) mutation was associated with 5 deaths related to atrial fibrillation and stroke among 12 mutation-positive members. Myosin heavy chain 7 gene (MYH7) mutation was associated with 11 deaths in 15 affected members. The clinical course was quite different for different HCM mutations. Even within the same family, individuals carrying the same mutation differed in disease expression and prognosis. Show less

To investigate the genotype-phenotype correlation in Chinese familial and sporadic hypertrophic cardiomyopathy, specific exons of the myosin binding protein-c gene (MYBPC3) were screened in six families with hypertrophic cardiomyopathy (HCM; FHCM) and in 20 patients with sporadic HCM (SHCM) from the Anhui Province region of China. The V896M mutation was detected for the first time in China in two families with FHCM. The mutation was not found in 100 healthy control subjects. No mutations of MYBPC3 were detected in any of the SHCM patients. In contrast to previous reports, the V896M mutation may be a disease-causing mutation in China, and exon 27 of MYBPC3 may be a mutational hotspot in FHCM patients. However, mutations of MYBPC3 were not prevalent among SHCM patients. Show less

In this part of a series on cardiogenetic founder mutations in the Netherlands, we review the Dutch founder mutations in hypertrophic cardiomyopathy (HCM) patients. HCM is a common autosomal dominant genetic disease affecting at least one in 500 persons in the general population. Worldwide, most mutations in HCM patients are identified in genes encoding sarcomeric proteins, mainly in the myosin-binding protein C gene (MYBPC3, OMIM #600958) and the beta myosin heavy chain gene (MYH7, OMIM #160760). In the Netherlands, the great majority of mutations occur in the MYBPC3, involving mainly three Dutch founder mutations in the MYBPC3 gene, the c.2373₂₃₇₄insG, the c.2864₂₈₆₅delCT and the c.2827C>T mutation. In this review, we describe the genetics of HCM, the genotype-phenotype relation of Dutch founder MYBPC3 gene mutations, the prevalence and the geographic distribution of the Dutch founder mutations, and the consequences for genetic counselling and testing. (Neth Heart J 2010;18:248-54.). Show less

Primary hypertrophic cardiomyopathy is a relatively frequent disease (1/500) which results from a mutation in a gene encoding a sarcomeric protein. In a series of 184 cases, nearly half (46 %) were secondary to a mutation in one of the 4 following genes : MYBPC3, MYH7, TNNI3, TNNT2. In Fabry disease, an exclusive or nearly exclusive cardiac expression is possible and referred to as "cardiac variant". The hypertrophic cardiomyopathy of Fabry disease is usually unspecific. Two series reported a prevalence of Fabry disease of about 6% among male cases. An Italian series of 34 female cases with hypertrophic cardiomyopathy demonstrated that it was feasible to diagnose Fabry disease in females by screening for specific lesions in myocardial biopsies. We detected a patient who initially presented with a common hypertrophic cardiomyopathy except that his ECG showed depression of ST segment and inversion of T wave in leads D1, VL and in precordial leads. The family history revealed several affected relatives and female carriers. In conclusion, an isolated common hypertrophic cardiomyopathy may be secondary to Fabry disease. Male patients should be screened systemically for enzyme defect except in cases of father-to-son transmission. In females, an affected male relative should be searched for screening or the GLA gene should be sequenced. It is important to think about a putative Fabry disease in cases with hypertrophic cardiomyopathy not associated with any obvious cause. Show less

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiovascular disorders. Mutations in the MYBPC3 gene are one of the most frequent genetic causes of HCM. To screen MYBPC3 gene mutations in Chinese patients with HCM, and analyze the correlation between the genotype and the phenotype. The 35 exons of the MYBPC3 gene were amplified by polymerase chain reaction in the 11 consecutive unrelated Chinese pedigrees. The sequences of the products were analyzed and the mutation sites were determined. The clinical data of genotype-positive families were collected, and the correlation between genotype and phenotype was analyzed. Two mutations of the MYBPC3 gene were confirmed among 11 pedigrees. A frameshift mutation (Pro459fs) was identified in exon 17 in family H8, and a splice mutation (IVS5+5G−>C) was identified in intron 5 in family H3. These two mutations were first identified in Chinese patients with familial HCM and were absent in 110 chromosomes of healthy controls. Seven known polymorphisms were found in the cohort. Compared with what was reported abroad, the MYBPC3 gene is a common pathogenic gene responsible for HCM in Chinese patients, and the phenotypes of these two mutations in their respective families may have their own clinical characteristics. Show less

Mutations in the cardiac myosin-binding protein C (MYBPC3) gene are frequently found as a cause of hypertrophic cardiomyopathy (HCM). However, only a few studies have analysed genotype-phenotype correlations in small series of patients. The present study sought to determine the clinical characteristics, penetrance and prognosis of HCM with an identical mutation in MYBPC3. 154 non-related patients with HCM (aged 55±16 years, 100 (64.9%) males) were studied. 18 (11.7%) were found to have an identical mutation in the MYBPC3 gene (IVS23+1G→A). Pedigree analysis, including both clinical evaluation and genotyping, was performed. 152 individuals (mean age 37±18 years, 53.3% males) from 18 families were evaluated. 65 carriers of the IVS23+1G→A mutation were identified, 61.5% of whom met HCM diagnostic criteria. Penetrance of the disease increased with age, with 50% affected at 46 years of age. Males tended to develop the disease earlier than females. 7 (15.6%) had systolic dysfunction. Compared with the rest of the HCM cohort, probands with the mutation had more hypertrophy and were younger at diagnosis. There was a trend towards a reduced survival free from sudden death (SD) (HR 1.71; 95% CI 0.98 to 2.98, p=0.059). There were 17 SD cases in 12 families with the mutation. The MYBPC3 IVS23+1G→A mutation is associated with middle-age onset disease and poor outcome, with a significant proportion of patients developing systolic impairment and a high SD risk profile. Show less

The MYBPC3-A31P mutation has been identified in the USA in a colony of Maine Coon cats with an autosomal dominant hypertrophic cardiomyopathy (HCM). The objectives of this prospective study were: 1) to evaluate the prevalence of this mutation in a large feline population from Europe; 2) to compare these data with the prevalence of HCM in the Maine Coon breed. 1) 3757 cats from different breeds including 2744 Maine Coon cats were screened for the mutation. 2) 164/2744 Maine Coon cats were subjected to echocardiography (Echo-Group, mean age = 2.6 years [0.3-11.5]). 1) In the whole study population, the mutation was only found in Maine Coon cats (prevalence = 41.5%), except for one British Longhair cat. 2) 55/164 (34%) cats from the Echo-Group carried the mutation while only 12/164 (7%; 5/48 heterozygous, 5/7 homozygous mutated, 2/109 homozygous wild-type cats) showed HCM. MYBPC3-A31P was associated with a significant increased risk of HCM (relative risk = 9.91). The MYBPC3-A31P mutation is highly prevalent in Maine Coon cats in Europe and appears to be breed specific with potential marginal events. Young unaffected mutated cats and affected homozygous wild-type cats illustrate the phenotypic and etiological heterogeneity of feline HCM, as demonstrated in humans. Show less

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease affecting 1 in 500 people. Due to large cohorts to investigate, the number of disease-causing genes, the size of the 2 prevalent mutated genes, and the presence of a large spectrum of private mutations, mutational screening must be performed using an extremely sensitive and specific scanning method. High Resolution Melting (HRM) analysis was developed for prevalent HCM-causing genes (MYBPC3, MYH7, TNNT2, and TNNI3) using control DNAs and DNAs carrying previously identified gene variants. A cohort of 34 HCM patients was further blindly screened. To evaluate HRM sensitivity, this cohort was also screened using an optimized DHPLC methodology. All gene variants detected by DHPLC were also readily identified as abnormal by HRM analysis. Mutational screening of a cohort of 34 HCM cases led to identification of 19 mutated alleles. Complete molecular investigation was completed two times faster and cheaper than using DHPLC strategy. HRM analysis represents an inexpensive, highly sensitive and high-throughput method to allow identification of mutations in the coding sequences of prevalent HCM genes. Identification of more HCM mutations will provide new insights into genotype/phenotype relationships and will allow a better knowledge of the HCM physiopathology. Show less

Hypertrophic cardiomyopathy (HCM) is a genetic disorder characterized by cardiac hypertrophy caused by mutations in sarcomere protein genes. MYBPC3 mutations are reported as a frequent cause of HCM. We aimed to identify the gene mutation underlying HCM in an Italian patient and his family composed of 13 relatives. Mutation screening of 658 known mutations was performed using a rapid and efficient mutation detection system based on semiautomated MALDI-TOF mass spectrometry using the Sequenom MassArray System and iPLEX Gold genotyping chemistry. Subsequently, direct sequencing of the coding exons and flanking intronic regions was performed for the most suitable HCM genes (MYBPC3, MYH7, TNNT2, TNNI3, and TPM1) in the index patient. We found a novel MYBPC3 gene mutation: G13999T (Gln689His). No other sarcomere gene mutation was found in this family. This genetic variant, which changes the last amino acid of MYBPC3 exon 21, affects a highly conserved residue. Furthermore, the Gln689His does not appear in public databases and has never been described as a polymorphism. The potential pathogenic role of this novel mutation was underlined by its absence in a sample of healthy subjects (n = 122) from the general Italian population. In summary, a novel MYBPC3 gene mutation has been identified in a patient affected by HCM, whereas it was absent in 244 reference alleles. Show less

Hypertrophic Cardiomyopathy (HCM), a common and clinically heterogeneous disease characterized by unexplained ventricular myocardial hypertrophy and a high risk of sudden cardiac death, is mostly caused by mutations in sarcomeric genes but modifiers genes may also modulate the phenotypic expression of HCM mutations. The aim of the current study was to report the frequency of single and multiple gene mutations in a large French cohort of HCM patients and to evaluate the influence of polymorphisms previously suggested to be potential disease modifiers in this myocardial pathology. We report the molecular screening of 192 unrelated HCM patients using denaturing high-performance liquid chromatography/sequencing analysis of the MYBPC3, MYH7, TNNT2 and TNNI3 genes. Genotyping of 6 gene polymorphisms previously reported as putative HCM modifiers (5 RAAS polymorphisms and TNF-α -308 G/A) was also performed. Seventy-five mutations were identified in 92 index patients (48%); 32 were novel. MYBPC3 mutations (25%) represent the most prevalent cause of inherited HCM whereas MYH7 mutations (12%) rank second in the pathogenesis. The onset age was older in patients carrying MYBPC3 mutations than in those with MYH7 mutations. The MYBPC3 IVS20-2A>G splice mutation was identified in 7% of our HCM population. Multiple gene mutations were identified in 9 probands (5%), highlighting the importance of screening other HCM-causing genes even after a first mutation has been identified, particularly in young patients with a severe phenotype. No single or cumulative genetic modifier effect could be evidenced in this HCM cohort. Show less

Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, increased ventricular stiffness and impaired diastolic filling. We investigated to what extent myocardial functional defects can be explained by alterations in the passive and active properties of human cardiac myofibrils. Skinned ventricular myocytes were prepared from patients with obstructive HCM (two patients with MYBPC3 mutations, one with a MYH7 mutation, and three with no mutation in either gene) and from four donors. Passive stiffness, viscous properties, and titin isoform expression were similar in HCM myocytes and donor myocytes. Maximal Ca(2+)-activated force was much lower in HCM myocytes (14 ± 1 kN/m(2)) than in donor myocytes (23 ± 3 kN/m(2); P<0.01), though cross-bridge kinetics (k(tr)) during maximal Ca(2)(+) activation were 10% faster in HCM myocytes. Myofibrillar Ca(2)(+) sensitivity in HCM myocytes (pCa(50)=6.40 ± 0.05) was higher than for donor myocytes (pCa(50)=6.09 ± 0.02; P<0.001) and was associated with reduced phosphorylation of troponin-I (ser-23/24) and MyBP-C (ser-282) in HCM myocytes. These characteristics were common to all six HCM patients and may therefore represent a secondary consequence of the known and unknown underlying genetic variants. Some HCM patients did however exhibit an altered relationship between force and cross-bridge kinetics at submaximal Ca(2+) concentrations, which may reflect the primary mutation. We conclude that the passive viscoelastic properties of the myocytes are unlikely to account for the increased stiffness of the HCM ventricle. However, the low maximum Ca(2+)-activated force and high Ca(2+) sensitivity of the myofilaments are likely to contribute substantially to any systolic and diastolic dysfunction, respectively, in hearts of HCM patients. Show less

Only a small fraction of large genomes such as that of the human contains the functional regions such as the exons, promoters, and polyA sites. A platform technique for selective enrichment of functional genomic regions will enable several next-generation sequencing applications that include the discovery of causal mutations for disease and drug response. Here, we describe a powerful platform technique, termed "functional genomic fingerprinting" (FGF), for the multiplexed genomewide isolation and analysis of targeted regions such as the exome, promoterome, or exon splice enhancers. The technique employs a fixed part of a uniquely designed Fixed-Randomized primer, while the randomized part contains all the possible sequence permutations. The Fixed-Randomized primers bind with full sequence complementarity at multiple sites where the fixed sequence (such as the splice signals) occurs within the genome, and multiplex amplify many regions bounded by the fixed sequences (e.g., exons). Notably, validation of this technique using cardiac myosin binding protein-C (MYBPC3) gene as an example strongly supports the application and efficacy of this method. Further, assisted by genomewide computational analyses of such sequences, the FGF technique may provide a unique platform for high-throughput sample production and analysis of targeted genomic regions by the next-generation sequencing techniques, with powerful applications in discovering disease and drug response genes. Show less

The R820W mutation in the MYBPC3 gene has been associated with the development of hypertrophic cardiomyopathy (HCM) in rag-doll cats, but had not been described in humans. To describe the phenotype associated with the R820W mutation identified in a human family. The R820W was identified by direct sequencing of the MYBPC3 gene in a 47 year old woman with HCM and left ventricular non-compaction (LVNC). Clinical and genetic studies of the R820W mutation were performed in her family. The index patient was homozygous for the mutation and had no additional mutations in the main sarcomeric genes (MYH7, TNNT2, TNNI3, and TPM1). She had HCM with LVNC and normal systolic function. One brother had died suddenly at age 43 years. Another brother diagnosed of LVNC with severe systolic dysfunction and a cardiac arrest was also homozygous for the mutation. One heterozygous 31 year old sister, and three heterozygous sons of the index (ages 14, 20 and 23 years old) were clinically unaffected. The father of the index was apparently healthy and her mother had atrial fibrillation and an electrocardiographic diagnosis of left ventricular hypertrophy at age 86 years. The R820W mutation in the MYBPC3 gene, previously associated with HCM in rag-doll cats, causes both HCM and LVNC in homozygous human carriers, with mild or null clinical expression in heterozygous carriers. Show less

Hypertrophic cardiomyopathy (HCM) is the prototypic form of pathological cardiac hypertrophy. HCM is an important cause of sudden cardiac death in the young and a major cause of morbidity in the elderly. We discuss the clinical implications of recent advances in the molecular genetics of HCM. The current diagnosis of HCM is neither adequately sensitive nor specific. Partial elucidation of the molecular genetic basis of HCM has raised interest in genetic-based diagnosis and management. Over a dozen causal genes have been identified. MYH7 and MYBPC3 mutations account for about 50% of cases. The remaining known causal genes are uncommon and some are rare. Advances in DNA sequencing techniques have made genetic screening practical. The difficulty, particularly in the sporadic cases and in small families, is to discern the causal from the non-causal variants. Overall, the causal mutations alone have limited implications in risk stratification and prognostication, as the clinical phenotype arises from complex and often non-linear interactions between various determinants. The clinical phenotype of 'HCM' results from mutations in sarcomeric proteins and subsequent activation of multiple cellular constituents including signal transducers. We advocate that HCM, despite its current recognition and management as a single disease entity, involves multiple partially independent mechanisms, despite similarity in the ensuing phenotype. To treat HCM effectively, it is necessary to delineate the underlying fundamental mechanisms that govern the pathogenesis of the phenotype and apply these principles to the treatment of each subset of clinically recognized HCM. Show less

The term peripartum cardiomyopathy (PPCM) describes dilated cardiomyopathy (DCM) without known cause that occurs during the last month of pregnancy to 5 months postpartum. A related term, pregnancy-associated cardiomyopathy (PACM), refers to DCM onset earlier in pregnancy. Multiple studies have focused on inflammatory, immunologic, and environmental causes. An alternative hypothesis is that PPCM and PACM result, in part, from a genetic cause. In this study, we sought to test the hypothesis that rare DCM-associated mutations underlie a proportion of PACM or PPCM cases. A systematic search of our DCM database designed for family-based genetic studies was undertaken for cases associated with pregnancy and the postpartum period; in the identified cases, clinical and molecular genetic data, including exonic and near intron/exon boundaries of DCM genes, were analyzed. Of 4110 women from 520 pedigrees in the Familial Dilated Cardiomyopathy Research Project database, we identified 45 cases of PPCM/PACM. Evidence of familial clustering with DCM was present in 23 unrelated cases. Of the 45 cases, 19 had been resequenced for known DCM genes, and 6 carried mutations. Five had PPCM, of which 3 were familial with mutations found in MYH7, SCN5A, and PSEN2, and 2 were sporadic with mutations in MYH6 and TNNT2. One case had PACM and carried a mutation in MYBPC3. These findings suggest that a proportion of PPCM/PACM cases results from a genetic cause. Show less

The cost of genomic information has fallen steeply, but the clinical translation of genetic risk estimates remains unclear. We aimed to undertake an integrated analysis of a complete human genome in a clinical context. We assessed a patient with a family history of vascular disease and early sudden death. Clinical assessment included analysis of this patient's full genome sequence, risk prediction for coronary artery disease, screening for causes of sudden cardiac death, and genetic counselling. Genetic analysis included the development of novel methods for the integration of whole genome and clinical risk. Disease and risk analysis focused on prediction of genetic risk of variants associated with mendelian disease, recognised drug responses, and pathogenicity for novel variants. We queried disease-specific mutation databases and pharmacogenomics databases to identify genes and mutations with known associations with disease and drug response. We estimated post-test probabilities of disease by applying likelihood ratios derived from integration of multiple common variants to age-appropriate and sex-appropriate pre-test probabilities. We also accounted for gene-environment interactions and conditionally dependent risks. Analysis of 2.6 million single nucleotide polymorphisms and 752 copy number variations showed increased genetic risk for myocardial infarction, type 2 diabetes, and some cancers. We discovered rare variants in three genes that are clinically associated with sudden cardiac death-TMEM43, DSP, and MYBPC3. A variant in LPA was consistent with a family history of coronary artery disease. The patient had a heterozygous null mutation in CYP2C19 suggesting probable clopidogrel resistance, several variants associated with a positive response to lipid-lowering therapy, and variants in CYP4F2 and VKORC1 that suggest he might have a low initial dosing requirement for warfarin. Many variants of uncertain importance were reported. Although challenges remain, our results suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients. National Institute of General Medical Sciences; National Heart, Lung And Blood Institute; National Human Genome Research Institute; Howard Hughes Medical Institute; National Library of Medicine, Lucile Packard Foundation for Children's Health; Hewlett Packard Foundation; Breetwor Family Foundation. Show less

MyBPC3 mutations are amongst the most frequent causes of hypertrophic cardiomyopathy, however, its prevalence varies between populations. They have been associated with mild and late onset disease expression. Our objectives were to establish the prevalence of MyBPC3 mutations and determine their associated clinical characteristics in our patients. Screening by Single Strand Conformation Polymorphisms (SSCP) and sequencing of the fragments with abnormal motility of the MyBPC3 gene in 130 unrelated consecutive HCM index cases. Genotype-Phenotype correlation studies were done in positive families. 16 mutations were found in 20 index cases (15%): 5 novel [D75N, V471E, Q327fs, IVS6+5G>A (homozygous), and IVS11-9G>A] and 11 previously described [A216T, R495W, R502Q (2 families), E542Q (3 families), T957S, R1022P (2 families), E1179K, K504del, K600fs, P955fs and IVS29+5G>A]. Maximum wall thickness and age at time of diagnosis were similar to patients with MYH7 mutations [25(7) vs. 27(8), p = 0.16], [46(16) vs. 44(19), p = 0.9]. Mutations in MyBPC3 are present in 15% of our hypertrophic cardiomyopathy families. Severe hypertrophy and early expression are compatible with the presence of MyBPC3 mutations. The genetic diagnosis not only allows avoiding clinical follow up of non carriers but it opens new possibilities that includes: to take preventive clinical decisions in mutation carriers than have not developed the disease yet, the establishment of genotype-phenotype relationship, and to establish a genetic diagnosis routine in patients with familial HCM. Show less

Hypertrophic cardiomyopathy (HC) is the most frequent cardiac hereditary disease, caused by mutations in sarcomere protein coding genes. Although more than 430 mutations have been identified in several continents and countries, there have been no reports of mutations in Brazil. To carry out a genetic study to identify genetic mutations that cause HC in a group of patients in Espirito Santo, Brazil. Using the SSCP technique, 12 exons from the three main genes involved in HC were studied: exons 15, 20, 21, 22 and 23 of the beta-myosin heavy chain gene (MYH7), exons 7, 16, 18, 22 and 24 of the myosin binding protein C gene (MYBPC3) and exons 8 and 9 of troponin T gene (TNNT2). 16 alterations were found, including two mutations, one of them possibly pathogenic in the MYBPC3 gene (p. Glu441Lys) and another pathogenic one, previously described in the TNNT2 gene (p.Arg92Trp), 8 rare sequence variations and 6 sequence variations with allelic frequency higher than 1% (polymorphisms). These data allow the conclusion that the genotyping of patients is feasible in our country. It is possible that the isolated p.Glu441Lys variant identified in exon 16 of the MYBPC3 gene is pathogenic, promoting a milder phenotype than that found when in association with other mutations. The p.Arg92Trp variant in the exon 9 of TNNT2 gene does not promote such a homogeneous phenotype as previously described and it can lead to severe hypertrophy. Show less

The myosin-binding protein C isoform 3 (MYBPC3) variant Arg502Trp has been identified in multiple hypertrophic cardiomyopathy (HCM) cases, but compelling evidence to support or refute the pathogenicity of this variant is lacking. To determine the prevalence, origin and clinical significance of the MYBPC3 Arg502Trp variant. The prevalence of MYBPC3 Arg502Trp was ascertained in 1414 sequential HCM patients of primarily European descent. MYBPC3 Arg502Trp was identified in 34 of these 1414 unrelated HCM patients. Segregation of MYBPC3 Arg502Trp with clinical status was assessed in family members. Disease haplotypes were examined in 17 families using two loci flanking MYBPC3. Family studies identified an additional 43 variant carriers, many with manifest disease, yielding a calculated odds ratio of 11 000:1 for segregation of MYBPC3 Arg502Trp with HCM. Analyses in 17 families showed at least 4 independent haplotypes flanked MYBPC3 Arg502Trp. Eight individuals (4 probands and 4 family members) also had another sarcomere protein gene mutation. Major adverse clinical events occurred in approximately 30% of MYBPC3 Arg502Trp carriers by age 50; these were significantly more likely (P<0.0001) when another sarcomere mutation was present. MYBPC3 Arg502Trp is the most common and recurrent pathogenic mutation in a diverse primarily European descent HCM cohort, occurring in 2.4% of patients. MYBPC3 Arg502Trp conveys a 340-fold increased risk for HCM by 45 years of age, when more than 50% of carriers have overt disease. HCM prognosis worsens when MYBPC3 Arg502Trp occurs in the setting of another sarcomere protein gene mutation. Show less

Heart failure is a leading cause of death of people in South Asia, and cardiomyopathy is a major cause of heart failure. Myosin binding protein C (MYBPC3) is expressed in the heart muscle, where it regulates the cardiac response to adrenergic stimulation and is important for the structural integrity of the sarcomere. Mutations in the MYBPC3 gene are associated with hypertrophic or dilated cardiomyopathies. A 25-base-pair deletion in intron 32 causes skipping of the downstream exon and is associated with familial cardiomyopathy. To date, this deletion is found primarily in India and South Asia, although it is also found at low frequency in Southeast Asia. In order to better characterise the distribution of this variant, we determined its frequency in 447 individuals from 19 populations, including 10 populations from India and neighbouring populations from Pakistan and Nepal. The deletion frequency is over 8% in some of our Indian samples, and it is not present in any of the populations we sampled outside of India. The differences in the deletion frequencies among populations in India are consistent with patterns of variation previously reported and with patterns we observed among Indian populations based on high-density SNP chip data. Our results indicate that the MYBPC3 deletion is primarily found among Indian populations and that its distribution is consistent with genome-wide patterns of variation in India. Show less

In patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF), radiofrequency catheter ablation (RFCA) represents a promising option. However, the predictors of RFCA efficacy remain largely unknown. We assessed the outcome of a multicentre HCM cohort following RFCA for symptomatic AF refractory to medical therapy. Sixty-one patients (age 54 +/- 13 years; time from AF onset 5.7 +/- 5.5 years) with paroxysmal (n = 35; 57%), recent persistent (n = 15; 25%), or long-standing persistent AF (n = 11; 18%) were enrolled. A scheme with pulmonary vein isolation plus linear lesions was employed. Of the 61 patients, 32 (52%) required redo procedures. Antiarrhythmic therapy was maintained in 22 (54%). At the end of a 29 +/- 16 months follow-up, 41 patients (67%) were in sinus rhythm, including 17 of the 19 patients aged < or = 50 years, with marked improvement in New York Heart Association (NYHA) functional class (1.2 +/- 0.5 vs. 1.9 +/- 0.7 at baseline; P < 0.001). In the remaining 20 patients (33%), with AF recurrence, there was less marked, but still significant, improvement following RFCA (NYHA class 1.8 +/- 0.7 vs. 2.3 +/- 0.7 at baseline; P = 0.002). Independent predictors of AF recurrence were increased left atrium volume [hazard ratio (HR) per unit increase 1.009, 95% confidence interval (CI) 1.001-1.018; P = 0.037] and NYHA functional class (HR 2.24, 95% CI 1.16-4.35; P = 0.016). Among 11 genotyped HCM patients (6 with MYBPC3, 2 with MYH7, 1 with MYL2 and 2 with multiple mutations), RFCA success rate was comparable with that of the overall cohort (n = 8; 73%). RFCA was successful in restoring long-term sinus rhythm and improving symptomatic status in most HCM patients with refractory AF, including the subset with proven sarcomere gene mutations, although redo procedures were often necessary. Younger HCM patients with small atrial size and mild symptoms proved to be the best RFCA candidates, likely due to lesser degrees of atrial remodelling. Show less