Variant Of Hypertrophic Cardiomyopathy Research Articles

Extended myectomy for apical hypertrophic cardiomyopathy: a case report

BackgroundApical hypertrophic cardiomyopathy is a variant of hypertrophic cardiomyopathy that predominantly affects the apex of the left ventricle and rarely involves the right ventricular apex or both apexes. Heart transplantation is the traditional treatment for apical hypertrophic cardiomyopathy. Although surgical myectomy approaching the apex has been available for decades, its safety and accuracy greatly depend on the surgeon’s skills and experience.Case presentationThe first case involved a 63-year-old man with apical hypertrophic cardiomyopathy, wherein preoperative contrast computed tomography findings revealed apical hypertrophy and complete apical cavity obliteration. The patient underwent extended myectomy, which revealed the apex cavity filled with abnormal muscles. Using the transaortic approach, the location of the bilateral papillary muscle was confirmed, thereby providing the required orientation. The abnormal muscle mass was successfully resected, and the postoperative end-diastolic volume was extremely increased. The second case involved a 43-year-old man with an apical left ventricular aneurysm and mid-hypertrophic cardiomyopathy obstruction. The thin-walled apical aneurysm contained a large apical-basal band. Upon detecting the bilateral papillary muscle, mid-ventricular myectomy was performed from the apex. During postoperative catheterization, there was no pressure gradient between the left ventricle and aorta.ConclusionsWe reviewed two cases of apical hypertrophic cardiomyopathy, efficiently treated using extended apical myectomy. Although it is an uncommon procedure, the cases presented show how it can be used to successfully manage cases of apical hypertrophic cardiomyopathy. However, it is important to secure the postoperative left ventricular end-diastolic volume.

Apical hypertrophic cardiomyopathy: contemporary view on the prevalence, clinical profile, diagnostic and treatmen (review of literature)

This review presents the last literature data, concerning prevalence, clinical profile, diagnostic and treatment of apical hypertrophic cardiomyopathy (HCM), as less known among «classical» variants of HCM. It is also discussed the rare form of apical HCM — mid-ventricular HCM with apical aneurism formation.

Survival analysis in hypertrophic cardiomyopathy caused by the three most common pathogenic TPM1 variants

Abstract Purpose To evaluate survival free of cardiovascular events in carriers of the three most frequent TPM1 pathogenic hypertrophic cardiomyopathy (HCM) variants. Methods Clinical and genetic data on families carrying TPM1 variants in the literature and identified in our center were systematically revised and collected in a database. Classification of variant's pathogenicity was in accordance with ACMG criteria. We evaluated available follow-up data and constructed Kaplan-Meier survival curves to cardiovascular death (sudden death, appropriate cardiodefibrillator shock, heart failure death, and stroke-related death) or heart transplant. Long-rank test was used to compare event-free survival time. Results 562 carriers (343 HCM-probands and 219 relatives; 51.3% male carriers) were identified carrying 73 missense variants considered disease causing. TPM1 p.Asp175Asn (87 probands, 109 relatives, 6 unaffected), p.Arg21Leu (52 probands, 25 relatives, 16 unaffected), and p.Met281Val (37 probands, 8 relatives, 9 unaffected) were the most prevalent HCM-variants. Among these three variants, survival data was reported for 508 individuals. Eight-nine carriers had suffered events: 74 sudden deaths (55% males), nine heart failure deaths (44% males), two transplants (50% males), and five stroke-related death (25% males). Incidence of cardiovascular death or transplant was similar between TPM1 p.Arg21Leu and p.Met281Val (p=0.75) and different than p.Asp175Asn (p=0.03 and p=0.06, respectively) and all TPM1 variants (p=0.004 and p=0.04). Analysis by sex showed TPM1 p.Arg21Leu female carriers had better prognosis than p.Asp175Asn male carriers (p=0.048) and all TPM1 male and female carriers (p=0.02 and p=0.04) (curves not showed in the graph). Conclusion TPM1 p.Arg21Leu and p.Met281Val could have a better prognosis than p.Asn175Asn and all other TPM1 missense variants in HCM. No marked difference was observed between male and female carriers. More than 80% of the events were arrhythmic deaths. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): HEALTH IN CODE SL

Prognosis of apical hypertrophic cardiomyopathy in patients with an implantable cardioverter defibrillator

Abstract Background Prophylactic use of implantable cardioverter-defibrillators (ICDs) to prevent sudden cardiac death (SCD) is widely spread all over the world in patients with hypertrophic cardiomyopathy (HCM). Apical HCM is a phenotype variant of HCM, with hypertrophy predominantly affecting apex, that was initially described 30 years ago. Apical HCM patients may have different clinical prognosis compared with other subsets of HCM. In previous studies, apical HCM patients seem to have a more benign prognosis than other types of HCM. However, little is known about the long-term outcomes of apical HCM and there are many unclear points. Moreover, there are few reports about the clinical prognosis in apical HCM patients with an ICD. Objective The aim of this study is to identify the difference between the prognosis of apical and the other HCM patients with an ICD. Methods We retrospectively analyzed the database of our ICD clinic. All subjects had been implanted with an ICD from October 2006 to August 2017. We classified HCM patients into LV outflow tract obstruction (LVOTO) and midventricular obstruction (MVO), apical HCM and other non-obstructive types. We divided all the patients into apical and other types of HCM, and examined their background, incidence of appropriate ICD therapies, hospitalization for heart failure, electrical storm and death. Results A total of consecutive 62 Japanese HCM patients with an ICD (follow-up period, 86±25 months; age, 67±14 years; male sex, 85%; left ventricular ejection fraction, 57±12%; LV max wall-thickness, 19±5mm; LV apical aneurysm, 9.7%; HCM Risk-SCD, 4.4±3.0) were enrolled in this study. We classified them into 14 apical HCM and 48 other types of HCM patients. The clinical characteristics and major events of these patients are shown in the Figure. During the follow-up periods, there were no significant differences in the incidence of hospitalization for heart failure, electrical storm and death between the 2 groups (p=0.40; p=0.22; p=0.23). Appropriate therapies occurred in 5 of 14 (36%) patients with apical HCM and 4 of 48 (8.3%) patients with other types of HCM (p=0.022). Conclusions Appropriate ICD therapy was more prevalent in patients with apical HCM, compared to patients with other types of HCM. However, the incidences of hospitalization for heart failure, electrical storm and death were not significantly different between two groups. Funding Acknowledgement Type of funding sources: None.

Abstract 402: Defining Diverse Disease Pathomechanisms Across Thick And Thin Filament Hypertrophic Cardiomyopathy Variants.

Hypertrophic cardiomyopathy (HCM) affects as many as ~1 in 500 individuals, and is often typified by hyperdynamic contraction and poor cellular relaxation. HCM can be caused by mutations in a variety of key contractile proteins of the sarcomere. A large proportion of these variants are found in MYBPC3, MYH7, TNNT2, and TNNI3. These genes encode proteins that control cardiac muscle contraction at the thick (MYBPC3 and MYH7) and thin filaments (TNNT2 and TNNI3) of the sarcomere. In this study we use human induced pluripotent stem cell derived cardiomyocytes to model HCM across all of these genes. We do this to define key mechanistic differences between thick and thin filament HCM. We define sarcomeric contractility (SarcTrack) calcium transients (CalTrack) and myosin states using the mant-ATP assay. We use the parametric data from these experimental studies in iPSC-CMs to model possible disease mechanisms in silico. Our experimental analysis highlights that both thick and thin filament HCM variants cause cellular hypercontractility, with slowed cellular relaxation. We find that thick filament HCM variants drive cellular HCM phenotypes by destabilising the myosin interacting heads motif (IHM), showing a marked reduction in the super relaxed state of myosin. Counterintuitively thin filament based HCM variants show a reduction in DRX myosin. When applying Mavacamten the allosteric myosin ATPase inhibitor to our thin and thick filament HCM variant iPSC-CMs we find a dichotomy of cellular responses. The thick filament variants studied all show a clear resolution of cellular HCM. However, not all cellular phenotypes of thin filament HCM are corrected by Mavacamten treatment, although there is benefit. We conclude that causal mechanisms of thick filament HCM are well corrected at the molecular and cellular level by Mavacamten, but these causal mechanisms in thin filament based HCM are not suitably corrected. We highlight key mechanistic pharmacological targets for thin filament variants that could add cellular benefit to HCM phenotype resolution.

Founder mutation in myosin-binding protein C with an early onset and a high penetrance in males

ObjectiveOne of the challenges in hypertrophic cardiomyopathy (HCM) is to determine the pathogenicity of genetic variants and to establish genotype/phenotype correlations. This study aimed to: (1) demonstrate that MYBPC3 c.2149–1G>A...

Myocardial Bridge or Something Else?

In this E-Challenge, the authors report on a patient with symptoms of exertional dyspnea and angina, scheduled to have surgical unroofing of an identified myocardial bridge (MB). An MB is very common in patients with hypertrophic cardiomyopathy (HCM). Intraoperative transesophageal echocardiography with provocative maneuvers revealed the patient had a systolic anterior motion of the mitral valve with septal contact and resulting outflow tract obstruction despite the notable absence of significant basal septal hypertrophy. HCM has many phenotypic variants that can make the identification of patients with latent left ventricular outflow tract obstruction difficult in the absence of a high index of suspicion. In this report, the authors discuss the association between MBs and HCM and the importance of recognizing phenotypic variants of HCM.

Variation p.R1045H in MYH7 correlated with hypertrophic cardiomyopathy in a Chinese pedigree

BackgroundInherited hypertrophic cardiomyopathy (HCM) is a common heart muscle disease that damages heart function and may cause the heart to suddenly stop beating. Genetic factors play an important role in HCM. Pedigree analysis is a good way to identify the genetic defects that cause disease.MethodsAn HCM pedigree was determined in Yunnan, China. Whole-exome sequencing was performed to identify the genetic variants of HCM. Another 30 HCM patients and 200 healthy controls were also used to investigate the frequency of the variants by customized TaqMan genotyping assay.ResultsThe variant NM_000257.4:c.3134G > A (NP_000248.2:p.Arg1045His, rs397516178, c.3134G > A in short) was found to cosegregate with the clinical phenotype of HCM. Moreover, the variant was not found in the 200 control subjects. After genotyping the variant in 30 HCM patients, there was one patient who carried the variant and had a family history.ConclusionsOur findings suggest that this variant may be closely related to the occurrence of the disease. According the ACMG guidelines, the c.3134G > A variant should be classified as "Likely pathogenic".

Whole-exome sequencing reveals MYH7 p.R671C mutation in three different phenotypes of familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (HCM) is one of the most common types of genetic heart disorder and features high genetic heterogeneity. HCM is a major cause of sudden cardiac death and also an important cause of heart failure-related disability. A pedigree with suspected familial HCM was recruited for the present study to identify genetic abnormalities. HCM was confirmed by echocardiography and clinical data of the family members were collected. Genomic DNA was extracted from the peripheral blood and sequenced based on standard whole-exome sequencing (WES) protocols. Sanger sequencing was further performed to verify mutation sites and their association with HCM. WES and Sanger sequencing revealed a heterozygous missense mutation (c.2011C>T p.R671C) in myosin heavy chain 7 (MYH7) that was identified in three family members. The Arg671Cys mutation was located in exon 18 and, to the best of our knowledge, has not been previously reported in familial HCM. Furthermore, family members carrying the same mutated gene were of different sexes and clinical phenotypes. They included the proband, a 17-year-old survivor of sudden cardiac arrest with ventricular systolic dysfunction, the proband's maternal uncle, who presented with ventricular diastolic dysfunction and the proband's mother, who had no obvious clinical symptoms and did not present with cardiac dysfunction. However, echocardiology indicated that the proband's mother had an enlarged left atrium, slightly thicker right anterior wall and anterior septum and an expanded atrial septum. Therefore, HCM exhibited obvious genetic and phenotypic heterogeneity. To the best of our knowledge, the present study was the first to report such a mutation in the MYH7 gene in familial HCM. In addition, the present study demonstrated that WES is a powerful tool for identifying genetic variants in HCM.

Assesment of Markers of Endothelial Dysfunction and Myocardial Stress in Patients with Hypertrophic Cardyomyopathy

Aim. To study the level of serum biomarkers of endothelial dysfunction and myocardial stress in patients with various types of hypertrophic cardiomyopathy (HCM).Material and Methods. 48 patients with hypertrophic cardiomyopathy (27 men and 21 women) were examined, the mean age was 54±13 years. The patients were divided into two groups according to the course options: group 1 - symptomatic stable course (n=14); group 2 - progressive course of symptomatic HCM (n=34). In accordance with the assigned tasks, all patients underwent determination of biological markers of neurohumoral systems in blood serum using immunofluorescence assay analysis: N-terminal fragment of brain natriuretic peptide (NT-proBNP), von Willebrand factor (vWF), endothelin-1, E-selectin with subsequent evaluation and correlation of results with clinical and instrumental characteristics of patients. When performing echocardiography following parameters were assessed: dimensions of the heart chambers, the thickness of the interventricular septum, the thickness of the posterior wall of the left ventricle (LV), LV mass, LV mass index, the ratio between LV filling in diastole (peak E) and atrial systole (peak A)-(E/A), relative myocardial thickness index, left atrial volume index.Results. Both groups showed increased levels of NT-proBNP and endothelin-1. E-selectin and vonWillebrand factor remained within the normal range. There was no statistically significant intergroup difference. There was a correlation between the level of the index of the relative myocardial thickness and the level of NT-proBNP (r=0.30; p=0.04). A correlation was found between the level of the vWF marker and the left atrial volume index (r=0.32; p=0.04). When assessing the association of indicators of intracardiac hemodynamics with other markers (E-selectin and endothelin-1, no statistically significant relationships were found.Conclusion. In the course of the research, it was found that the high activity of endothelin-1 and NT-proBNP reflects endothelial dysfunction and myocardial stress in patients with HCM, especially in patients with a progressive variant of HCM. However, we did not find any changes in the levels of E-selectin and von Willebrand factor, as well as their intergroup differences. These results require additional studies to assess endothelial dysfunction in patients with HCM.

Redução septal não alcoólica em caso de cardiomiopatia hipertrófica com uso de coils

In patients with the obstructive variant of hypertrophic cardiomyopathy, when symptomatic despite the medical therapy, septal reduction is a common treatment option. Among all the percutaneous approaches, therapeutic septal alcoholization is the most commonly used technique. Non-alcoholic septal reduction techniques have recently emerged as an additional treatment option, generating procedures with more predictable outcomes and lower complication rates. In this report, we describe a case of therapeutic septal reduction with embolization of the target branch using coils with excellent immediate results.

Role of MRI in Hypertrophic Cardiomyopathy with Midventricular Obstruction and Apical Aneurysm: Uncommon High-risk Variant

Hypertrophic cardiomyopathy (HCM) is characterized by cardiac muscle hypertrophy, unexplained by loading conditions with a nondilated left ventricle and normal or increased ejection fraction Midventricular obstruction of the left ventricle is an increasingly recognized phenotypic variant of hypertrophic cardiomyopathy due to the widespread availability of Cardiac Magnetic Resonance Imaging (CMR). Mid ventricular obstruction with apical aneurysm is a high risk variant of HCM which can lead to higher risk of arrhythmia and SCD. This variant is clinically and prognostically significant with MRI playing a major role in detection. CMR has nearly 100 % sensitivity in diagnosis and also helps in identifying other high risk features. CMR is helpful in detecting Late gadolinium enhancement (LGE) and apical aneurysm for which echocardiography is less sensitive. LGE represent area of replacement fibrosis which can act as a source for life threatening arrhythmia. Although this variant is not considered high risk feature for sudden cardiac death (SCD) in HCM cohort according to standard guideline, it is increasingly being recognized as a high risk feature by recent studies. Treatment is controversial however patients with multiple risk factors of SCD can be treated with ICD implantation to prevent catastrophic events. Herein we present a case of HCM with midventricular obstruction where MRI showed apical aneurysm with scarring and midventricular gradient. Incidence, pathophysiology, diagnosis role of CMR and treatment of this variant of HCM is discussed.

Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients.

To assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry. We sequenced HCM disease genes in Singaporean patients (n=224) and Singaporean controls (n=3634), compared findings with additional populations and White HCM cohorts (n=6179), and performed in vitro functional studies. Singaporean HCM patients had significantly fewer confidently interpreted HCM disease variants (pathogenic/likely pathogenic: 18%, P<0.0001) but an excess of variants of uncertain significance (24%, P<0.0001), as compared to Whites (pathogenic/likely pathogenic: 31%, excess of variants of uncertain significance: 7%). Two missense variants in thin filament encoding genes were commonly seen in Singaporean HCM (TNNI3:p.R79C, disease allele frequency [AF]=0.018; TNNT2:p.R286H, disease AF=0.022) and are enriched in Singaporean HCM when compared with Asian controls (TNNI3:p.R79C, Singaporean controls AF=0.0055, P=0.0057, genome aggregation database-East Asian AF=0.0062, P=0.0086; TNNT2:p.R286H, Singaporean controls AF=0.0017, P<0.0001, genome aggregation database-East Asian AF=0.0009, P<0.0001). Both these variants have conflicting annotations in ClinVar and are of low penetrance (TNNI3:p.R79C, 0.7%; TNNT2:p.R286H, 2.7%) but are predicted to be deleterious by computational tools. In population controls, TNNI3:p.R79C carriers had significantly thicker left ventricular walls compared with noncarriers while its etiological fraction is limited (0.70 [95% CI, 0.35-0.86]) and thus TNNI3:p.R79C is considered variant of uncertain significance. Mutant TNNT2:p.R286H iPSC-CMs (induced pluripotent stem cells derived cardiomyocytes) show hypercontractility, increased metabolic requirements, and cellular hypertrophy and the etiological fraction (0.93 [95% CI, 0.83-0.97]) support the likely pathogenicity of TNNT2:p.R286H. As compared with Whites, Chinese HCM patients commonly have low penetrance risk alleles in TNNT2 or TNNI3 but exhibit few clinically actionable HCM variants overall. This highlights the need for greater study of HCM genetics in non-White populations.

Reevaluation of the South Asian MYBPC3Δ25bp Intronic Deletion in Hypertrophic Cardiomyopathy.

The common intronic deletion, MYBPC3Δ25, detected in 4% to 8% of South Asian populations, is reported to be associated with cardiomyopathy, with ≈7-fold increased risk of disease in variant carriers. Here, we examine the contribution of MYBPC3Δ25 to hypertrophic cardiomyopathy (HCM) in a large patient cohort. Sequence data from 2 HCM cohorts (n=5393) was analyzed to determine MYBPC3Δ25 frequency and co-occurrence of pathogenic variants in HCM genes. Case-control and haplotype analyses were performed to compare variant frequencies and assess disease association. Analyses were also undertaken to investigate the pathogenicity of a candidate variant MYBPC3 c.1224-52G>A. Our data suggest that the risk of HCM, previously attributed to MYBPC3Δ25, can be explained by enrichment of a derived haplotype, MYBPC3Δ25/-52, whereby a small subset of individuals bear both MYBPC3Δ25 and a rare pathogenic variant, MYBPC3 c.1224-52G>A. The intronic MYBPC3 c.1224-52G>A variant, which is not routinely evaluated by gene panel or exome sequencing, was detected in ≈1% of our HCM cohort. The MYBPC3 c.1224-52G>A variant explains the disease risk previously associated with MYBPC3Δ25 in the South Asian population and is one of the most frequent pathogenic variants in HCM in all populations; genotyping services should ensure coverage of this deep intronic mutation. Individuals carrying MYBPC3Δ25 alone are not at increased risk of HCM, and this variant should not be tested in isolation; this is important for the large majority of the 100 million individuals of South Asian ancestry who carry MYBPC3Δ25 and would previously have been declared at increased risk of HCM.

Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations. We assayed myosin ATP binding to define the proportion of myosins in the super relaxed state (SRX) conformation or the disordered relaxed state (DRX) conformation in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology, we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants of unknown clinical significance that were identified in patients with HCM, predicted functional consequences and associations with heart failure and arrhythmias. Myosins undergo physiological shifts between the SRX conformation that maximizes energy conservation and the DRX conformation that enables cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacological modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased the proportion of myosins in the SRX conformation, whereas pathogenic variants destabilized these and increased the proportion of myosins in the DRX conformation, which enhanced cardiomyocyte contractility, but impaired relaxation and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify variants of unknown clinical significance, we showed that the variants that destabilized myosin conformations were associated with higher rates of heart failure and arrhythmias in patients with HCM. Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy-conserving states promotes contractile abnormalities, morphological and metabolic remodeling, and adverse clinical outcomes in patients with HCM. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in patients with HCM.

Case Study: Dilated Cardiomyopathy Evolves into Apical-Variant Hypertrophic Cardiomyopathy

Introduction Apical-variant hypertrophic cardiomyopathy (HCM) is a form of HCM in which hypertrophy is limited to the left-ventricular apex. Apical-variant HCM is rarely obstructive, though there is still an increased risk of atrial fibrillation, myocardial infarction, and sudden cardiac death (SCD). Apical-variant HCM has not previously been described in a patient with a prior diagnosis of dilated cardiomyopathy (DCM). Case A 53-year-old female with a history of hypertension and type-II diabetes mellitus presented with progressive dyspnea on exertion, fatigue and lower extremity swelling. Family history was significant for SCD of her mother at age 45. An initial transthoracic echocardiogram (TTE) showed DCM with an ejection fraction (EF) 15% and left ventricular end diastolic dimension (LVEDD) of 6.8 cm. The patient was placed on guideline-directed medical therapy (GDMT) and ultimately received cardiac resynchronization therapy with a defibrillator (CRT-D). One year later, EF was 25% with LVEDD 7.1 cm (Figure 1). A subsequent TTE two years later showed resolution of DCM with EF 55% and LVEDD of 5.1 cm. However, a new finding on this TTE was apparent: the apex demonstrated a spade-like shape on contraction consistent with apical-variant HCM (Figure 2). The patient underwent genetic testing but no genetic cause of either DCM or HCM was identified. Discussion HCM is caused by autosomal-dominant inheritance of a defective gene in sarcomere proteins. DCM and HCM are linked in that some etiologies of DCM are driven by sarcomeric protein abnormalities. DCM is also a rare phenotypical variant of HCM generally occurring very late in the disease and evolving from an initially hypertrophic myocardium. The opposite, in which DCM evolves into apical-variant HCM, to the best of our knowledge, has not been described in the literature. This relationship, as well as a family history of early SCD, suggest an inherited sarcomeric disorder manifesting as two discrete phenotypes within the same individual. This evolution may be due to treatment with GDMT, or it may be a rare expression of the disease's natural history. Only a fraction of cases of idiopathic DCM and HCM have an identifiable genetic cause and, thus, lacking an identified mutation does not preclude an inherited cardiomyopathy.

Highlights From the Circulation Family of Journals.

Highlights From the Circulation Family of Journals.

Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes.

Genetic testing for families with hypertrophic cardiomyopathy (HCM) provides a significant opportunity to improve care. Recent trends to increase gene panel sizes often mean variants in genes with questionable association are reported to patients. Classification of HCM genes and variants is critical, as misclassification can lead to genetic misdiagnosis. We show the validity of previously reported HCM genes using an established method for evaluating gene-disease associations. A systematic approach was used to assess the validity of reported gene-disease associations, including associations with isolated HCM and syndromes including left ventricular hypertrophy. Genes were categorized as having definitive, strong, moderate, limited, or no evidence of disease causation. We also reviewed current variant classifications for HCM in ClinVar, a publicly available variant resource. Fifty-seven genes were selected for curation based on their frequent inclusion in HCM testing and prior association reports. Of 33 HCM genes, only 8 (24%) were categorized as definitive ( MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3); 3 had moderate evidence ( CSRP3, TNNC1, and JPH2; 33%); and 22 (66%) had limited (n=16) or no evidence (n=6). There were 12 of 24 syndromic genes definitively associated with isolated left ventricular hypertrophy. Of 4191 HCM variants in ClinVar, 31% were in genes with limited or no evidence of disease association. The majority of genes previously reported as causative of HCM and commonly included in diagnostic tests have limited or no evidence of disease association. Systematically curated HCM genes are essential to guide appropriate reporting of variants and ensure the best possible outcomes for HCM families.

Quantitative approaches to variant classification increase the yield and precision of genetic testing in Mendelian diseases: the case of hypertrophic cardiomyopathy

BackgroundInternational guidelines for variant interpretation in Mendelian disease set stringent criteria to report a variant as (likely) pathogenic, prioritising control of false-positive rate over test sensitivity and diagnostic yield. Genetic testing is also more likely informative in individuals with well-characterised variants from extensively studied European-ancestry populations. Inherited cardiomyopathies are relatively common Mendelian diseases that allow empirical calibration and assessment of this framework.MethodsWe compared rare variants in large hypertrophic cardiomyopathy (HCM) cohorts (up to 6179 cases) to reference populations to identify variant classes with high prior likelihoods of pathogenicity, as defined by etiological fraction (EF). We analysed the distribution of variants using a bespoke unsupervised clustering algorithm to identify gene regions in which variants are significantly clustered in cases.ResultsAnalysis of variant distribution identified regions in which variants are significantly enriched in cases and variant location was a better discriminator of pathogenicity than generic computational functional prediction algorithms. Non-truncating variant classes with an EF ≥ 0.95 were identified in five established HCM genes. Applying this approach leads to an estimated 14–20% increase in cases with actionable HCM variants, i.e. variants classified as pathogenic/likely pathogenic that might be used for predictive testing in probands’ relatives.ConclusionsWhen found in a patient confirmed to have disease, novel variants in some genes and regions are empirically shown to have a sufficiently high probability of pathogenicity to support a “likely pathogenic” classification, even without additional segregation or functional data. This could increase the yield of high confidence actionable variants, consistent with the framework and recommendations of current guidelines. The techniques outlined offer a consistent and unbiased approach to variant interpretation for Mendelian disease genetic testing. We propose adaptations to ACMG/AMP guidelines to incorporate such evidence in a quantitative and transparent manner.

A chance encounter with a case of hypertrophic cardiomyopathy.

A chance encounter with a case of hypertrophic cardiomyopathy.