Genetic Basis Of Hypertrophic Cardiomyopathy Research Articles

Genetic Basis of Hypertrophic Cardiomyopathy in Cats.

Hypertrophic cardiomyopathy (HCM) is a common cardiovascular condition in cats, affecting yth males and females of all ages. Some breeds, such as Ragdolls and Maine Coons, can develop HCM at a young age. The disease has a wide range of progression and severity, characterized by various pathological changes in the heart, including arteritis, fibrous tissue deposition, and myocardial cell hypertrophy. Left ventricular hypertrophy, which can restrict blood flow, is a common feature of HCM. The disease may persist into old age and eventually lead to heart failure and increased diastolic pressure. The basis of HCM in cats is thought to be genetic, although the exact mechanisms are not fully understood. Mutations in sarcomeric proteins, in particular myosin-binding protein C (MYBPC3), have been identified in cats with HCM. Two specific mutations, MYBPC3 [R818W] and MYBPC3 [A31P], have been classified as 'pathogenic'. Other variants in genes such as MYBPC3, TNNT2, ALMS1, and MYH7 are also associated with HCM. However, there are cases where cats without known genetic mutations still develop HCM, suggesting the presence of unknown genetic factors contributing to the disease. This work aims to summarise the new knowledge of HCM in cats and the alterations in cardiac tissue as a result of genetic variants.

Relationship Between Genotype Status and Clinical Outcome in Hypertrophic Cardiomyopathy.

The genetic basis of hypertrophic cardiomyopathy (HCM) is complex, and the relationship between genotype status and clinical outcome is incompletely resolved. We assessed a large international HCM cohort to define in contemporary terms natural history and clinical consequences of genotype. Consecutive patients (n=1468) with established HCM diagnosis underwent genetic testing. Patients with pathogenic (or likely pathogenic) variants were considered genotype positive (G+; n=312; 21%); those without definite disease-causing mutations (n=651; 44%) or variants of uncertain significance (n=505; 35%) were considered genotype negative (G-). Patients were followed up for a median of 7.8 years (interquartile range, 3.5-13.4 years); HCM end points were examined by cumulative event incidence. Over follow-up, 135 (9%) patients died, 33 from a variety of HCM-related causes. After adjusting for age, all-cause and HCM-related mortality did not differ between G- versus G+ patients (hazard ratio [HR], 0.78 [95% CI, 0.46-1.31]; P=0.37; HR, 0.93 [95% CI, 0.38-2.30]; P=0.87, respectively). Adverse event rates, including heart failure progression to class III/IV, heart transplant, or heart failure death, did not differ (G- versus G+) when adjusted for age (HR, 1.20 [95% CI, 0.63-2.26]; P=0.58), nor was genotype independently associated with sudden death event risk (HR, 1.39 [95% CI, 0.88-2.21]; P=0.16). In multivariable analysis, age was the only independent predictor of all-cause and HCM-related mortality, heart failure progression, and sudden death events. In this large consecutive cohort of patients with HCM, genotype (G+ or G-) was not a predictor of clinical course, including all-cause and HCM-related mortality and risk for heart failure progression or sudden death. G+ status should not be used to dictate clinical management or predict outcome in HCM.

Clinical significance and genetic basis of hypertrophic cardiomyopathy with apical phenotype: comparison of pure-apical form and distal-dominant form

Abstract Background Apical hypertrophic cardiomyopathy (apical HCM) is a variant of HCM first reported in Japan. The definition of apical HCM in the Japanese Circulation Society guideline is left ventricular hypertrophy limited to the level of the apex below the papillary muscle level. On the other hand, apical HCM in Western countries often includes hypertrophy that extends to the ventricular septum beyond the true LV apex. Although these variations may have different clinical characteristics and prognoses, they are often considered the same. Therefore, we previously proposed two phenotypes of apical HCM. Pure-apical form follows the definition of the JCS guideline. Distal-dominant form is defined as demonstrating apical hypertrophy extended to the ventricular septum without basal septal hypertrophy. However, the clinical significance and genetic basis of these phenotypes have not been reported. This study aimed to clarify clinical differences and yield of genetic testing in apical phenotype of HCM. Methods Regarding clinical presentation and prognosis, we retrospectively investigated 111 consecutive HCM patients with apical phenotype. HCM-related adverse events were defined as HCM-related death and nonfatal HCM-related events: heart failure admission, embolic stroke admission, and sustained ventricular tachycardia with hemodynamic instability or appropriate implantable cardioverter-defibrillator discharge. Furthermore, we performed a genetic analysis including 145 genes associated with cardiomyopathy in 69 unrelated patients within the cohort. Results In the cohort, 60 patients were pure-apical, and 51 were distal-dominant. The age at diagnosis was about 60 years, and the majority were male in both groups. The comorbidity rate of hypertension did not indicate a statistically significant difference. During the follow-up period of 10.3 ± 6.9 years, the occurrence of HCM-related adverse events was significantly higher in the distal-dominant group than in the pure-apical group (log-rank p=0.007). Detection rate of pathogenic or likely pathogenic variants in sarcomeric protein-encoding genes was significantly higher in the distal-dominant group than in the pure-apical group (21% vs. 3%; p=0.044). Conclusions Two phenotypes of apical HCM should be recognized and distinguished clinically because they have different prognoses and genetic features.

Mortality in hypertrophic cardiomyopathy is unrelated to genotype

Abstract Background Hypertrophic cardiomyopathy (HCM) patients with a pathogenic variant are presumed to have worse prognosis than patients without a pathogenic mutation. However, the genetic basis of hypertrophic cardiomyopathy (HCM) is complex, and relationship between genotype status and outcomes have not been completely resolved. Objective We assessed a large international HCM cohort to define the natural history and clinical consequences of genotype status. Methods Consecutive patients (n=1468) with established clinical HCM diagnosis underwent genetic testing focused on HCM-related genes. Patients with pathogenic or likely pathogenic variants were considered genotype positive (G+), and those without definite disease-causing mutation or a variant of uncertain significance (VUS) were considered genotype negative (G-). Patients were followed for 9.6 ± 8.2 years for clinical outcomes. Results Of 1468 HCM patients, 1156 (79%) were G - and 312 (21%) were G+. Over the follow-up 116 (10%) G- patients died at 70 ± 14 years, including in 26 (2.2%) from HCM-related causes. HCM-related mortality was not significantly different in G- patients (0.3%/year) as compared to G+ patients (0.3%/year) when adjusted for age (HR 0.93, 95% CI 0.38-2.30, p=0.87). All-cause mortality was not different among these groups (0.7%/year G- vs. 0.6%/year G+) when adjusted for age (HR 0.62, 95% CI 0.3-1.2, p=0.14) or comorbidities (HR 0.78, 95% CI 0.46-1.31, p=0.35). Rate of progression to advanced heart failure NYHA class III/IV in nonobstructive patients was not different in G- (4%/ year) vs. G+ (3%/year, HR 1.20, 95% CI 0.63-2.26, p=0.58). Sudden death events (appropriate ICD shocks, aborted cardiac arrest and sudden death) were more frequent in G+ patients (1.7%/year) than in G- patients (0.5%/year), albeit of borderline statistical significance when adjusted for age and SD risk factors (HR 1.58, 95% CI 1.00-2.49, p=0.05). Conclusions In this large consecutive genotyped cohort, all-cause and HCM-related mortality was unrelated to genotype status. Substantial proportion of G- patients experienced progressive HF, at a similar rate when compared to G+ patients. Although G- patients had less frequently SD events, genotype negative status could not be considered benign.FiguresTable

Abstract P2036: Induced Pluripotent Stem Cell- Derived Cardiomyocytes Provide New Insights Of The Pathogenic Consequences Of The Novel Frameshift Variant (c.5769delG) In MYH7 Gene

Background: the genetic basis of hypertrophic cardiomyopathy is pleiotropic; A novel disease causing frameshift variant (c.5769delG, MYH7 ) in the beta-myosin heavy chain gene has been recently described. However, the mechanisms involved have not been adequately defined. We have used iPSC-CMs to investigate the underlying mechanisms. Methods: We have generated patient-specific iPSCs from clinically and genetically defined HCM patients carrying the pathogenic variant (c.5769delG) (n=3) and compared them to iPSCs from healthy controls (n=3). Optical mapping of calcium transients and cell action potential were performed under different stimulation conditions. iPSC-CMs contractility was recorded via widefield microscopy. Gene and protein expression analyses were performed using RT-PCR, immunoblotting and immunocytochemistry. RNA sequencing data from patients’ myocardial tissues was analyzed to validate gene expression data from iPSC-CMs. Results: HCM iPSCs-CMs showed a significant decrease in calcium release duration (i.e., time to peak) with decrease in calcium transient amplitude, compared to controls. This was associated with an accelerated contraction and a decreased contraction amplitude. Nonetheless, action potential analysis showed no significant changes. Transcriptome analysis of iPSC-CMs and patients’ myocardial tissues showed a significant down regulation of SERCA/ATP2A2 , MYH6 and KCNIP2 . Conclusion: iPSC-CMs provided new insights of the pathogenic consequences of the novel variant in MYH7 gene on calcium handling and contractility. Key words: Hypertrophic Cardiomyopathy, Disease model, MYH7 , iPSC-CMs, Calcium Handling, Contractility.

Abstract 13383: Is Genotype Negative Hypertrophic Cardiomyopathy Really Benign? The Increased Risk of Sudden Death and Advanced Heart Failure in the Absence of Pathogenic Sarcomere Mutations

Introduction: The genetic basis of hypertrophic cardiomyopathy (HCM) is complex, and the genotype-phenotype correlations have not been completely resolved. Patients lacking a pathogenic variant are presumed to have a better prognosis than patients with sarcomeric pathogenic mutations. Aim: We sought to assess the relationship between the genotype status and the adverse clinical events. Methods: Consecutive patients with HCM underwent genetic testing focused on HCM-related genes. Patients with pathogenic or likely pathogenic variants were considered genotype positive (G+), and those without definite disease-causing mutation were considered genotype negative (G-). Patients were followed for 5.2 ±4.9 years for outcomes. Sudden death (SD) events included out-of-hospital cardiac arrests, appropriate ICD interventions, and HCM-related death. Results: Of 988 HCM patients, 212 (21%) were G+, while 776 (79%) were G -. As compared to G-, G+ HCM patients were younger (45 ± 14 vs. 53 ± 13 years), had more extensive LV hypertrophy (maximum wall thickness: 19.6 ± 5 mm vs. 18.4 ± 4 mm, p<0.001), and with no difference in the presence of LVOT obstruction (59% vs. 66%, p=0.06). Despite G- status, 3% of G- patients had extensive scarring on cardiac MRI (≥15% of LV mass; no different from G+, p=0.54). Over follow-up, 66 patients had SD events. While SD events were more common in G+ patients (11.3% vs. 5.4%, p=0.002), the majority of SD events occurred in G- patients (64%). Similarly, end-stage HCM developed 54 patients, more commonly in G+ (9.0% vs. 4.5%, p=0.01), but with majority of events in G- patients (65%). Conclusion: Contrary to certain prevailing views, in this large consecutive genotyped HCM cohort, sarcomere genotype-negative patients (representing a distinctive majority) did not express an entirely benign prognosis. In fact, nearly two-thirds of SD events and end-stage HF progression occurred in G- HCM patients, albeit at somewhat lower rates than in G+ patients. These data do not support that genotype should not be included as a risk marker of adverse arrhythmic and advanced heart failure events.

Single-cell transcriptomics provides insights into hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a genetic heart disease that is characterized by unexplained segmental hypertrophy that is usually most pronounced in the septum. While sarcomeric gene mutations are often the genetic basis for HCM, the mechanistic origin for the heterogeneous remodeling remains largely unknown. A better understanding of the gene networks driving the cardiomyocyte (CM) hypertrophy is required to improve therapeutic strategies. Patients suffering from HCM often receive a septal myectomy surgery to relieve outflow tract obstruction due to hypertrophy. Using single-cell RNA sequencing (scRNA-seq) on septal myectomy samples from patients with HCM, we identify functional links between genes, transcription factors, and cell size relevant for HCM. The data show the utility of using scRNA-seq on the human hypertrophic heart, highlight CM heterogeneity, and provide a wealth of insights into molecular events involved in HCM that can eventually contribute to the development of enhanced therapies.

Apical Hypertrophic Cardiomyopathy: The Variant Less Known.

Hypertrophic cardiomyopathy (HCM) is an umbrella term for a heterogeneous heart muscle disease that was historically (and still is) defined by the detection of left ventricular (LV) hypertrophy (LVH) in the absence of abnormal cardiac loading conditions. Long after this morphological definition was established, the genetic basis of HCM was discovered, and we now know it is predominantly caused by autosomal dominant mutations in sarcomeric protein genes.1 Several patterns of LVH have been described in HCM: asymmetric septal (here referred to as “classic” HCM), concentric, reverse septal, neutral, and apical (ApHCM),2 as well as other, rarer LVH variants such as isolated lateral LVH and isolated inferoseptal LVH. Distinguishing between morphological HCM subtypes has conferred little in terms of personalized management strategies, with one distinctive exception: ApHCM. Compared with classic HCM, ApHCM is more sporadic, sarcomere mutations are detected less frequently, there is more atrial fibrillation (AF) and sudden cardiac death (SCD) risk factors differ. No authoritative ApHCM‐specific recommendations to guide diagnosis, family screening, and patient risk stratification currently exist. First described in Japan in 1976,2 ApHCM is exemplified by “giant” negative precordial T‐waves on electrocardiography and by “spadelike” configuration of its LV cavity in end diastole.3 This review summarizes the epidemiology, clinical expression, genetics, and prognosis of ApHCM, while also highlighting knowledge gaps

Sarcomere variants in arrhythmogenic cardiomyopathy: Pathogenic factor or bystander?

BackgroundArrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disease, which is mainly caused by desmosomal mutations. Sarcomere variants were the primary genetic basis of hypertrophic cardiomyopathy (HCM) and were recently detected in arrhythmogenic cardiomyopathy (ACM). Our aim is to seek potential pathogenic variants of sarcomere genes in our ACM cohort and describe their characteristics. MethodsWe performed targeted sequencing of 14 sarcomere genes in 84 patients with ACM and set strict criteria to identify potential pathogenic variants. Clinical screening was performed on all available family members of the patients carrying sarcomere variants and specific variants were tested in screened family members by Sanger sequencing. ResultsWe identified 6 sarcomere variants in 6 (7%) patients, which were all definite ACM. Sarcomere variants were detected in NEBL, MYH7, MYH6 and TNNI3, with low prevalence in controls and predicted pathogenic in silico. Among these patients, three had previous detected PKP2 variants. Patients with sarcomere variants all experienced major arrhythmic cardiac event (MACE) with the average age of the first documented MACE being 41.2 ± 11.0 years. Pedigrees analysis showed none of the sarcomere variants carriers among the family members were affected, indicating very low penetrance. ConclusionsWe detected some sarcomere variants in our ACM cohort. Although those patients with sarcomere variants had severe arrhythmic burden, family co-segregation analysis didn't strongly support a primary role in the pathogenesis of ACM.

Genetic basis of hypertrophic cardiomyopathy in children.

Previous investigations assessing the genetic cause of pediatric hypertrophic cardiomyopathy (HCM) found underlying genetic mutations in 50-60% of cases. The purpose of our study was to analyze whether this number can be augmented by applying next-generation sequencing and directing further diagnostics by discussing unsolved cases in a multidisciplinary board. 42 patients with the diagnoses of HCM made before age 18years were treated in our center from 2000 to 2016. Genetic analysis was performed in 36 subjects, a genetic defect was detected in 29 (78%) patients. 15 individuals (42%) had pathogenic variants in genes encoding sarcomere proteins, and 5 (14%) in genes coding for components of the RAS/MAPK signaling pathway. 4 subjects (11%) had mutations in the GAA gene (Pompe disease), and 3 (8%) had Frataxin repeat expansions (Friedreich's ataxia). One patient each showed a mutation in BAG3 and LMNA. Discussion of unsolved HCM cases after performing next-generation sequencing (28 genes) in an interdisciplinary board unraveled the genetic cause in 9 subjects (25%). A definite genetic diagnosis can be reached in nearly 80% with HCM of childhood onset. Next-generation sequencing in conjunction with a multidisciplinary cooperation can enhance the diagnostic yield substantially. This may be important for risk stratification, treatment planning and genetic counseling.

Mitochondrial Dysfunctions Contribute to Hypertrophic Cardiomyopathy in Patient iPSC-Derived Cardiomyocytes with MT-RNR2 Mutation.

SummaryHypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death in young individuals. A potential role of mtDNA mutations in HCM is known. However, the underlying molecular mechanisms linking mtDNA mutations to HCM remain poorly understood due to lack of cell and animal models. Here, we generated induced pluripotent stem cell-derived cardiomyocytes (HCM-iPSC-CMs) from human patients in a maternally inherited HCM family who carry the m.2336T>C mutation in the mitochondrial 16S rRNA gene (MT-RNR2). The results showed that the m.2336T>C mutation resulted in mitochondrial dysfunctions and ultrastructure defects by decreasing the stability of 16S rRNA, which led to reduced levels of mitochondrial proteins. The ATP/ADP ratio and mitochondrial membrane potential were also reduced, thereby elevating the intracellular Ca2+ concentration, which was associated with numerous HCM-specific electrophysiological abnormalities. Our findings therefore provide an innovative insight into the pathogenesis of maternally inherited HCM.

Abstract 397: Generation of Raf1 Mutant and Crispr-cas9 Corrected Isogenic iPSC-derived Cardiomyocytes to Model Hypertrophic Cardiomyopathy in Noonan Syndrome

Background: Hypertrophic cardiomyopathy (HCM) is a major cause of death in infants and children. Noonan Syndrome (NS), an autosomal dominant RASopathy disorder, is characterized by multiple defects, including short stature, facial dysmorphia, and congenital heart defects that include HCM. RASopathies are caused by germ-line mutations that affect the canonical RAS-MAPK pathway. Indeed, 95% of NS patients with a mutation in Raf1 , a gene that plays an integral role in this signaling cascade, exhibit HCM. However, the molecular mechanisms that elicit HCM in these patients remain poorly understood. Objective: To generate human NS Raf1 induced-pluripotent stem cells (iPSCs), correct the mutation by genome editing and subsequently differentiate isogenic iPSC lines into cardiomyocytes to characterize the molecular and genetic basis of HCM in NS patients. Results: We generated iPSCs from skin fibroblasts obtained from a NS pediatric patient with a single point mutation in the Raf1 gene. Using electroporation of four episomal vectors containing the Yamanaka factors, we obtained several iPSC clones with normal karyotypes and strong expression of pluripotent markers (Nanog, Oct4, Lin28, Sox2) as detected by RT-qPCR and immunofluorescence. We next corrected the mutation in the NS Raf1 iPSCs using genome editing CRISPR-Cas9 nickase technology. Correction of the Raf1 mutation was determined at the clonal level by PCR followed by Restriction Fragment Length Polymorphism and confirmed by Sanger sequencing. In addition, by inducing a Cas9 nickase-dependent frame shift mutation we also generated an isogenic iPSC line where Raf1 gene was knockout (KO), as demonstrated at the RNA level by RT-qPCR and at the protein level by Western Blot. We next differentiated these multiple iPSC lines (mutant, corrected and KO) into isogenic beating cardiomyocytes, with more >98% of the cells positive for specific cardiomyocyte markers (α-actinin and cardiac TroponinT). Conclusion: We have successfully generated human NS Raf1 isogenic iPSC lines and corresponding cardiomyocytes. Currently, we are in progress of characterizing these cardiac cells to determine the molecular basis of NS-dependent HCM. Ultimately, our work should reveal new targets to treat HCM in NS patients.

Rapid molecular genetic diagnosis of hypertrophic cardiomyopathy by semiconductor sequencing.

BackgroundRapidly determining the complex genetic basis of Hypertrophic cardiomyopathy (HCM) is vital to better understanding and optimally managing this common polygenetic cardiovascular disease.MethodsA rapid custom Ion-amplicon-resequencing assay, covering 30 commonly affected genes of HCM, was developed and validated in 120 unrelated patients with HCM to facilitate genetic diagnosis of this disease. With this HCM-specific panel and only 20 ng of input genomic DNA, physicians can, for the first time, go from blood samples to variants within a single day.ResultsOn average, this approach gained 595628 mapped reads per sample, 95.51% reads on target (64.06 kb), 490-fold base coverage depth and 93.24% uniformity of base coverage in CDS regions of the 30 HCM genes. After validation, we detected underlying pathogenic variants in 87% (104 of 120) samples. Tested seven randomly selected HCM genes in eight samples by Sanger sequencing, the sensitivity and false-positive-rate of this HCM panel was 100% and 5%, respectively.ConclusionsThis Ion amplicon HCM resequencing assay provides a currently most rapid, comprehensive, cost-effective and reliable measure for genetic diagnosis of HCM in routinely obtained samples.

Muscle dysfunction in hypertrophic cardiomyopathy: What is needed to move to translation?

Hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere genes. As such, HCM provides remarkable opportunities to study how changes to the heart's molecular motor apparatus may influence cardiac structure and function. Although the genetic basis of HCM is well-described, there is much more limited understanding of the precise consequences of sarcomere mutations--how they remodel the heart, and how these changes lead to the dramatic clinical consequences associated with HCM. More precise characterization of the mechanisms leading from sarcomere mutation to altered cardiac muscle function is critical to gain insight into fundamental disease biology and phenotypic evolution. Such knowledge will help foster development of novel treatment strategies aimed at correcting and preventing disease development in HCM.

Expanding the Genetic Spectrum of Hypertrophic Cardiomyopathy: X Marks the Spot

During the past 25 years, major advances have been made in our understanding of the genetic basis of hypertrophic cardiomyopathy (HCM). Although being a disease that was defined as a tumor of the heart by Donald Teare in 1958,1 our genetic advances have led to a complete redefinition of HCM as a complex nonsyndromic genetic disorder characterized by unexplained left ventricular hypertrophy, in the absence of loading conditions. To date, >1300 mutations in ≥13 disease genes have been identified in patients with HCM.2 These disease genes encode primarily sarcomere and sarcomere-related proteins and are almost exclusively inherited in an autosomal dominant pattern, with some isolated reports of autosomal recessive HCM.3 Collectively, these findings have led to the description of HCM as a disease of the sarcomere.4 Although current genetic testing strategies in HCM lead to an overall pathogenic mutation detection rate of ≤50%, the presence of a family history of HCM and sudden death because of HCM can increase the mutation detection rate to >75%.5 However, many families with HCM have no causative mutation identified. To this end, efforts to identify the remaining as yet unidentified genes are to be commended and are at the forefront of novel gene discoveries in HCM. Article see p 543 In this issue of Circulation: Cardiovascular Geneti cs, Hartmannova et al6 present findings from a large 4-generation Czech family characterized by 4 male individuals with nonobstructive HCM with severe left ventricular diastolic dysfunction and evidence of end-stage disease. Two of these 4 men required heart transplantation. In an attempt to identify a …

New paradigms in hypertrophic cardiomyopathy: Insights from genetics

Understanding the genetic basis of hypertrophic cardiomyopathy (HCM) provides a remarkable opportunity to predict and prevent disease. HCM is caused by mutations in sarcomere genes and is the most common monogenic cardiovascular disorder. Although unexplained left ventricular hypertrophy (LVH) is considered diagnostic, LVH is not always present. LV wall thickness is often normal until adolescence or later, even in individuals known to carry pathogenic sarcomere mutations. In contrast, genetic testing can identify both individuals who carry pathogenic sarcomere mutations and have a clinical diagnosis of HCM, as well as mutation carriers who have not yet manifested LVH but are very likely to develop disease. Studying this important new patient subset, designated early or preclinical HCM, allows characterization of the initial consequences of sarcomere mutations, prior to the onset of overt hypertrophic remodeling. Such study has defined novel early phenotypes, including impaired left ventricular relaxation, myocardial energetic deficiencies, and altered collagen metabolism, in mutation carriers with apparently normal cardiac morphology. These results indicate that sarcomere mutations have substantial impact on myocardial function and biochemistry before the onset of frank hypertrophy. Furthermore, animal models of preclinical HCM have identified promising new treatment strategies that may diminish the emergence of overt disease. We can now begin to reshape the paradigm for treating genetic disorders. With improved mechanistic insight and the capability for early diagnosis, genetic advances can lead to new approaches for disease modification and prevention.

Analysis of the Z-disc genes PDLIM3 and MYPN in Patients with Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a disease characterised by genetic heterogeneity with over 1000 different mutations identified, primarily in genes encoding sarcomere or sarcomere-related proteins. DNA sequencing of the 8 most common causal genes in HCM identifies a mutation in about 50% of cases [ 1 Lind J.M. Chiu C. Semsarian C. Genetic basis of hypertrophic cardiomyopathy. Expert Rev Cardiovasc Ther. 2006; 4: 927-934 Crossref PubMed Scopus (42) Google Scholar , 2 Maron B.J. Semsarian C. Emergence of gene mutation carriers and the expanding disease spectrum of hypertrophic cardiomyopathy. Eur Heart J. 2010; 31: 1551-1553 Crossref PubMed Scopus (32) Google Scholar ], with large gene deletions and insertions unlikely to play a role in the pathogenesis of HCM [ [3] Bagnall R.D. Yeates L. Semsarian C. The role of large gene deletions and duplications in MYBPC3 and TNNT2 in patients with hypertrophic cardiomyopathy. Int J Cardiol. 2009; (Aug 8 [Epub ahead of print]) PubMed Google Scholar ]. These results suggest a large proportion of HCM mutations reside in novel causal genes.

Sarcomere Gene Mutations in Hypertrophy and Heart Failure

Despite considerable progress in identifying and modifying risk factors that cause cardiovascular disease, heart failure has emerged as an important medical and socioeconomic problem. Hypertrophic remodeling, a common response to many cardiovascular disorders, increases the risk of heart failure. Discovery of the genetic basis of hypertrophic cardiomyopathy has allowed consideration of whether these genes also contribute to pathologic remodeling that occurs in the context of common acquired cardiovascular disorders. Evidence supporting a shared etiology has emerged from the recent identification of sarcomere protein mutations and sequence variants in community-based populations with hypertrophy and heart failure. These findings imply that harnessing genetic testing for hypertrophic mutations may help define patients at risk for heart failure. In the future, mechanistic insights into hypertrophic remodeling, combined with strategies to prevent this pathology, are expected to reduce the burden of heart failure.

Overlapping Phenotypes

Patient KM is a 26-year-old male in whom a systolic ejection murmur was recently identified on a routine physical examination. As part of his evaluation, he underwent 2-dimensional echocardiography, which revealed asymmetrical left ventricular (LV) hypertrophy with a maximum LV wall thickness of 22 mm in the basal anterior septum and extension of hypertrophy into the posterior septum. His LV ejection fraction was 55%, with a normal cavity size and no evidence of resting LV outflow tract obstruction. In addition, the myocardium was noted to be highly trabeculated from the apex to the midportion of the LV (Figure 1; online-only Data Supplement Movie I). The right ventricle was normal in size and function. He has never developed heart failure …

Array-Based Resequencing Assay for Mutations Causing Hypertrophic Cardiomyopathy

Background: Dissecting the complex genetic basis of hypertrophic cardiomyopathy (HCM) may be key to both better understanding and optimally managing this most prevalent genetic cardiovascular disease. An array-based resequencing (ABR) assay was developed to facilitate genetic testing in HCM.Methods: An Affymetrix resequencing array and a single long-range PCR protocol were developed to cover the 3 most commonly affected genes in HCM, MYH7 (myosin, heavy chain 7, cardiac muscle, beta), MYBPC3 (myosin binding protein C, cardiac), and TNNT2 [troponin T type 2 (cardiac)].Results: The assay detected the underlying point mutation in 23 of 24 reference samples and provided pointers toward identifying a G insertion and a 3-bp deletion. The comparability of array-based assay results to conventional capillary sequencing was ≥99.9%. Both techniques detected 1 heterozygous variant that was missed by the other method.Conclusions: The data provide evidence that ABR can substantially reduce the high workload previously associated with a genetic test for HCM. Therefore, the HCM array could facilitate large-scale studies aimed at broadening the understanding of the genetic and phenotypic diversity of HCM and related cardiomyopathies.