FREQUENCY OF METABOLIC GENE MUTATIONS IN PATIENTS REFERRED FOR HYPERTROPHIC CARDIOMYOPATHY GENETIC TESTING

Coronary microvascular dysfunction (CMD) is an important primary feature of hypertrophic cardiomyopathy (HCM), contributing to myocardial ischemia and ventricular remodelling, and is predictive of adverse outcome. Whether there is any association between presence/severity of CMD and HCM’s pathogenic substrate remains to be determined. To address this issue, we used positron emission tomography (PET) to assess CMD in an HCM cohort that received comprehensive genetic testing for sarcomeric/myofilament-HCM. We measured maximum (intravenous dipyridamole, 0.56 mg/kg) myocardial blood flow (Dip-MBF), using 13 N-labeled ammonia and PET in 46 HCM patients (age 38±14 years, 32 male). Genetic testing was performed by denaturing high performance liquid chromatography and automatic DNA sequencing of nine myofilament-encoding genes including both thick filament proteins (myosin binding protein C, beta-myosin heavy chain, regulatory and essential light chains); and thin filament proteins (troponin-T, troponin-I, troponin-C, alpha-tropomyosin and alpha-actin). Results . Thirty-four mutations were identified in 30/46 patients (myofilament-HCM; 65%), including 29 with thick filament and 6 with thin filament mutations, as well as 4 with complex genotype. Despite similar age and clinical features, patients with myofilament-HCM showed lower Dip-MBF values than the patients with a negative genetic test (1.6±0.7 versus 2.2±0.9 ml/min/g, respectively; p=0.03). Specifically, 13/30 (43%) patients with myofilament-HCM had a Dip-MBF below the lower tertile for the study group (≤1.38 ml/min/g), compared to 2/16 (12%) patients with a negative genetic test (p=0.034). No difference in Dip-MBF was evident with respect to the particular sarcomeric gene involved (ANOVA p=0.63). HCM due to sarcomere gene mutations is characterized by more severe impairment in microvascular function compared to myofilament negative disease, irrespective of the involved contractile protein. These findings suggest that sarcomeric mutations might be implicated in adverse remodelling of the microcirculation in patients with HCM, and account for the greater prevalence of ventricular dysfunction and failure in this subset.

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Combined PTPN11 and MYBPC3 Gene Mutations in an Adult Patient with Noonan Syndrome and Hypertrophic Cardiomyopathy

Genes ◽

10.3390/genes11080947 ◽

2020 ◽

Vol 11 (8) ◽

pp. 947 ◽

Cited By ~ 2

Author(s):

Martina Caiazza ◽

Marta Rubino ◽

Emanuele Monda ◽

Annalisa Passariello ◽

Adelaide Fusco ◽

...

Keyword(s):

Genetic Testing ◽

Hypertrophic Cardiomyopathy ◽

Noonan Syndrome ◽

Gene Mutations ◽

Compound Heterozygous ◽

Ptpn11 Gene ◽

Etiological Diagnosis ◽

Atypical Case ◽

Mybpc3 Gene

In this report, an atypical case of Noonan syndrome (NS) associated with sarcomeric hypertrophic cardiomyopathy (HCM) in a 33-year-old patient was described. Genetic testing revealed two different disease-causing mutations: a mutation in the PTPN11 gene, explaining NS, and a mutation in the MYBPC3 gene, known to be associated with HCM. This case exemplifies the challenge in achieving a definite etiological diagnosis in patients with HCM and the need to exclude other diseases mimicking this condition (genocopies or phenocopies). Compound heterozygous mutations are rare but possible in HCM patients. In conclusion, this study highlights the important role of genetic testing as a necessary diagnostic tool for performing a definitive etiological diagnosis of HCM.

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Sarcomere mutation negative hypertrophic cardiomyopathy is associated with ageing and obesity

Open Heart ◽

10.1136/openhrt-2020-001560 ◽

2021 ◽

Vol 8 (1) ◽

pp. e001560

Author(s):

Alejandro E de Feria ◽

Andrew E Kott ◽

Jason R Becker

Keyword(s):

Genetic Testing ◽

Hypertrophic Cardiomyopathy ◽

Family History ◽

Myocardial Hypertrophy ◽

Gene Mutations ◽

Ventricular Outflow Tract ◽

Left Ventricular ◽

Left Ventricular Outflow ◽

History Of ◽

Clinical Phenotyping

BackgroundDespite advances in our understanding of the genetic causes of hypertrophic cardiomyopathy (HCM), a large portion of this patient population do not carry sarcomere gene mutations when screened. It remains largely unknown why patients without sarcomere mutations develop asymmetric myocardial hypertrophy.MethodsWe performed a retrospective analysis of probands with HCM who underwent genetic testing to determine if clinical phenotypes were different depending on sarcomere mutation status. A medical history, three generation family history and clinical phenotyping were performed on 127 probands with HCM. Genetic screening was performed using clinically available HCM genetic testing panels.ResultsWe found that probands with HCM with pathogenic sarcomere mutations were over three times more likely to have a family history of HCM (66% vs 17%, p<0.0001) and were diagnosed with HCM at a much younger age (32 vs 51 years old, p<0.0001). In contrast, probands with HCM without sarcomere mutations were significantly more obese (body surface area p=0.003, body mass index p=0.04 adjusted for age) and were more likely to present with left ventricular outflow tract obstruction (p=0.0483).ConclusionPatients with sarcomere mutation negative HCM present at an older age and are more obese compared with patients with sarcomere mutation positive HCM. The role of ageing and obesity in asymmetric myocardial hypertrophy warrants further investigation.

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Serial Observations and Mutational Analysis of an Adoptee with Family History of Hypertrophic Cardiomyopathy

Cardiology Research and Practice ◽

10.4061/2010/697269 ◽

2010 ◽

Vol 2010 ◽

pp. 1-4

Author(s):

Bronwyn Harris ◽

Jean P. Pfotenhauer ◽

Cheri A. Silverstein ◽

Larry W. Markham ◽

Kim Schafer ◽

...

Keyword(s):

Genetic Testing ◽

Hypertrophic Cardiomyopathy ◽

Family History ◽

Mutational Analysis ◽

Clinical Findings ◽

Dominant Mode ◽

Natural Mother ◽

History Of ◽

In Cis ◽

Inherited Cardiac Disease

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disease with an autosomal dominant mode of transmission. Comprehensive genetic screening of several genes frequently found mutated in HCM is recommended for first-degree relatives of HCM patients. Genetic testing provides the means to identify those at risk of developing HCM and to institute measures to prevent sudden cardiac death (SCD). Here, we present an adoptee whose natural mother and maternal relatives were known be afflicted with HCM and SCD. The proband was followed closely from age 6 to 17 years, revealing a natural history of the progression of clinical findings associated with HCM. Genetic testing of the proband and her natural mother, who is affected by HCM, revealed that they were heterozygous for both the R719Q and T1513S variants in the cardiac beta-myosin heavy chain (MYH7) gene. The proband's ominous family history indicates that the combination of the R719Q and T1513S variantsin cismay be a “malignant” variant that imparts a poor prognosis in terms of the disease progression and SCD risk.

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

Journal of Molecular Medicine ◽

10.1007/s00109-005-0722-9 ◽

2005 ◽

Vol 83 (10) ◽

pp. 837-837 ◽

Cited By ~ 1

Author(s):

Andreas Perrot ◽

Hajo Schmidt-Traub ◽

Bernard Hoffmann ◽

Matthias Prager ◽

Nana Bit-Avragim ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Myosin Heavy Chain ◽

Heavy Chain ◽

Gene Mutations ◽

Chain Gene ◽

Heavy Chain Gene ◽

Myosin Heavy Chain Gene

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Multicenter Study of the Prevalence and Distribution of Sarcometric Gene Mutations in Familial Hypertrophic Cardiomyopathy

Circulation Journal ◽

10.1253/circj.cj-11-1260 ◽

2012 ◽

Vol 76 (2) ◽

pp. 303-304 ◽

Cited By ~ 1

Author(s):

Shinichi Niwano

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Multicenter Study ◽

Gene Mutations ◽

Familial Hypertrophic Cardiomyopathy

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839-5 Two transgenic animal models expressing human troponin T gene mutations: One exhibiting dilated cardiomyopathy (W141) and the other exhibiting hypertrophic cardiomyopathy (Q92)

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(04)90916-3 ◽

2004 ◽

Vol 43 (5) ◽

pp. A216 ◽

Cited By ~ 1

Author(s):

Jasvinder Sidhu ◽

Duanxiang Li ◽

Zhinong Wang ◽

A.J Marian ◽

Francesco J DeMayo ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Animal Models ◽

Dilated Cardiomyopathy ◽

Troponin T ◽

Gene Mutations ◽

Transgenic Animal ◽

The Other ◽

Transgenic Animal Models

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Clinical Profile and Health Disparities in a Multiethnic Cohort of Patients With Hypertrophic Cardiomyopathy

Circulation Heart Failure ◽

10.1161/circheartfailure.120.007537 ◽

2021 ◽

Vol 14 (3) ◽

Author(s):

Alexandra Butters ◽

Caitlin R. Semsarian ◽

Richard D. Bagnall ◽

Laura Yeates ◽

Fergus Stafford ◽

...

Keyword(s):

Health Disparities ◽

Genetic Testing ◽

Hypertrophic Cardiomyopathy ◽

Ethnic Groups ◽

South Asians ◽

Middle Eastern ◽

East Asian ◽

North African ◽

East Asians ◽

Cardioverter Defibrillator

Background: Clinical studies of hypertrophic cardiomyopathy are over-represented by individuals of European ethnicity, with less known about other ethnic groups. We investigated differences between patients in a multiethnic Australian hypertrophic cardiomyopathy population. Methods: We performed a retrospective cohort study of 836 unrelated hypertrophic cardiomyopathy probands attending a specialized clinic between 2002 and 2020. Major ethnic groups were European (n=611), East Asian (n=75), South Asian (n=58), and Middle Eastern and North African (n=68). The minor ethnicity groups were Oceanian (n=9), People of the Americas (n=7), and African (n=8). One-way ANOVA with Dunnett post hoc test and Bonferroni adjustment were performed. Results: Mean age of the major ethnic groups was 54.9±16.9 years, and 527 (65%) were male. Using the European group as the control, East Asian patients had a lower body mass index (29 versus 25 kg/m 2 , P <0.0001). South Asians had a lower prevalence of atrial fibrillation (10% versus 31%, P =0.024). East Asians were more likely to have apical hypertrophy (23% versus 6%, P <0.0001) and Middle Eastern and North African patients more likely to present with left ventricular outflow tract obstruction (46% versus 34%, P =0.0003). East Asians were less likely to undergo genetic testing (55% versus 85%, P <0.0001) or have an implantable cardioverter-defibrillator implanted (19% versus 36%, P =0.037). East Asians were more likely to have a causative variant in a gene other than MYBPC3 or MYH7 , whereas Middle Eastern and North African and South Asians had the highest rates of variants of uncertain significance (27% and 21%, P <0.0001). Conclusions: There are few clinical differences based on ethnicity, but importantly, we identify health disparities relating to access to genetic testing and implantable cardioverter-defibrillator use. Unless addressed, these gaps will likely widen as we move towards precision-medicine–based care of individuals with hypertrophic cardiomyopathy.

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Case Report of a 33-year-old with Ebstein malformation of tricuspid valve and hypertrophic cardiomyopathy

Cardiology in the Young ◽

10.1017/s1047951121003644 ◽

2021 ◽

pp. 1-2

Author(s):

Sedigheh Saedi ◽

Pooneh Pashapour ◽

Golnaz Houshmand

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Tricuspid Valve ◽

Cardiac Death ◽

Rare Case ◽

Protein Gene ◽

Gene Mutations ◽

Left Ventricular ◽

Congenital Disease ◽

Ventricular Cardiomyopathy ◽

Sarcomeric Protein

Abstract Ebstein malformation of tricuspid valve is a congenital disease of tricuspid valve with associated right ventricular cardiomyopathy. Hypertrophic cardiomyopathy is a form of inherited left ventricular cardiomyopathy caused by sarcomeric protein gene mutations with inherent risks of sudden cardiac death. Here we report a rare case with co-occurrence of Ebstein malformation of tricuspid valve and hypertrophic cardiomyopathy in a young patient.

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