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Evaluation of the Mayo Clinic Phenotype-Based Genotype Predictor Score in Patients with Clinically Diagnosed Hypertrophic Cardiomyopathy.

ABSTRACT: Genetic testing for hypertrophic cardiomyopathy (HCM) can provide an important clinical marker for disease outcome and family screening. This study set out to validate our recently developed phenotype-based HCM genotype predictor score. Patients clinically diagnosed with HCM and evaluated by genetic counselors comprised the study cohort. Genotype score was derived based on clinical and echocardiographic variables. Total score was correlated with the yield of genetic testing. Of 564 HCM patients, 198 sought genetic testing (35 %; 55 % male; mean age at diagnosis, 50?±?20 years). Of these, 101 patients (51 %) were genotype positive for a HCM-associated genetic mutation (55 % male; mean age at diagnosis, 42?±?18 years). Cochran-Armitage analysis showed similar, statistically significant trends of increased yields for higher genotype scores for both the original and study cohort. Validated by the current study, this scoring system provides an easy-to-use, clinical tool to aid in determining the likelihood of a positive HCM genetic test.

SUBMITTER: Murphy SL

PROVIDER: S-EPMC4907543 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Evaluation of the Mayo Clinic Phenotype-Based Genotype Predictor Score in Patients with Clinically Diagnosed Hypertrophic Cardiomyopathy.

Murphy Sinead L SL Anderson Jason H JH Kapplinger Jamie D JD Kruisselbrink Teresa M TM Gersh Bernard J BJ Ommen Steve R SR Ackerman Michael J MJ Bos J Martijn JM

Journal of cardiovascular translational research 20160225 2

Genetic testing for hypertrophic cardiomyopathy (HCM) can provide an important clinical marker for disease outcome and family screening. This study set out to validate our recently developed phenotype-based HCM genotype predictor score. Patients clinically diagnosed with HCM and evaluated by genetic counselors comprised the study cohort. Genotype score was derived based on clinical and echocardiographic variables. Total score was correlated with the yield of genetic testing. Of 564 HCM patients, ...[more]

PMID: 26914223

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Project description:Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease that affects approximately one in 500 people. HCM is a recognized genetic disorder most often caused by mutations involving myosin-binding protein C (MYBPC3) and ?-myosin heavy chain (MYH7) which are responsible for approximately three-quarters of the identified mutations.Methods: As a part of the international multidisciplinary SILICOFCM project ( www.silicofcm.eu ) the present study evaluated the association between underlying genetic mutations and clinical phenotype in patients with HCM. Only patients with confirmed single pathogenic mutations in either MYBPC3 or MYH7 genes were included in the study and divided into two groups accordingly. The MYBPC3 group was comprised of 48 patients (76%), while the MYH7 group included 15 patients (24%). Each patient underwent clinical examination and echocardiography.Results: The most prevalent symptom in patients with MYBPC3 was dyspnea (44%), whereas in patients with MYH7 it was palpitations (33%). The MYBPC3 group had a significantly higher number of patients with a positive family history of HCM (46% vs. 7%; p?=?0.014). There was a numerically higher prevalence of atrial fibrillation in the MYH7 group (60% vs. 35%, p?=?0.085). Laboratory analyses revealed normal levels of creatinine (85.5?±?18.3 vs. 81.3?±?16.4 µmol/l; p?=?0.487) and blood urea nitrogen (10.2?±?15.6 vs. 6.9?±?3.9 mmol/l; p?=?0.472) which were similar in both groups. The systolic anterior motion presence was significantly more frequent in patients carrying MYH7 mutation (33% vs. 10%; p?=?0.025), as well as mitral leaflet abnormalities (40% vs. 19%; p?=?0.039). Calcifications of mitral annulus were registered only in MYH7 patients (20% vs. 0%; p?=?0.001). The difference in diastolic function, i.e. E/e' ratio between the two groups was also noted (MYBPC3 8.8?±?3.3, MYH7 13.9?±?6.9, p?=?0.079).Conclusions: Major findings of the present study corroborate the notion that MYH7 gene mutation patients are presented with more pronounced disease severity than those with MYBPC3.

Project description:IntroductionIn clinical and animal studies, Hypertrophic Cardiomyopathy (HCM) shares many similarities with non-inherited cardiac hypertrophy induced by pressure overload (hypertension). This suggests a potential role for mechanical stress in priming tissues with mutation-induced changes in the sarcomere to develop phenotypes associated with HCM, including hypercontractility and aberrant calcium handling. Here, we tested the hypothesis that heterozygous loss of function of Myosin Binding Protein C (MYBCP3 +/- , mutations in which account for almost 50% of inherited HCM) combines with environmental stiffness to drive HCM phenotypes.MethodsWe differentiated isogenic control (WTC) and MYBPC3 +/- iPSC into cardiomyocytes using small molecule manipulation of Wnt signaling, and then purified them using lactate media. The purified cardiomyocytes were seeded into "dog bone" shaped stencil molds to form micro-heart muscle arrays (μHM). To mimic changes in myocardial stiffness stemming from pressure overload, we varied the rigidity of the substrates μHM contract against. Stiffness levels ranged from those corresponding to fetal (5 kPa), healthy (15 kPa), pre-fibrotic (30 kPa) to fibrotic (65 kPa) myocardium. Substrates were embedded with a thin layer of fluorescent beads to track contractile force, and parent iPSC were engineered to express the genetic calcium indicator, GCaMP6f. High speed video microscopy and image analysis were used to quantify calcium handling and contractility of μHM.ResultsSubstrate rigidity triggered physiological adaptation for both genotypes. However, MYBPC3 +/- μHM showed a lower tolerance to substrate stiffness with the peak traction on 15 kPa, while WTC μHM had peak traction on 30 kPa. MYBPC3 +/- μHM exhibited hypercontractility, which was exaggerated by substrate rigidity. MYBPC3 +/- μHM hypercontractility was associated with longer rise times for calcium uptake and force development, along with higher overall Ca2+ intake.ConclusionWe found MYBPC3 +/- mutations cause iPSC-μHM to exhibit hypercontractility, and also a lower tolerance for mechanical stiffness. Understanding how genetics work in combination with mechanical stiffness to trigger and/or exacerbate pathophysiology may lead to more effective therapies for HCM.Supplementary informationThe online version contains supplementary material available at (10.1007/s12195-021-00684-x).

Dataset Information

Evaluation of the Mayo Clinic Phenotype-Based Genotype Predictor Score in Patients with Clinically Diagnosed Hypertrophic Cardiomyopathy.

Publications

Evaluation of the Mayo Clinic Phenotype-Based Genotype Predictor Score in Patients with Clinically Diagnosed Hypertrophic Cardiomyopathy.

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