Characterization of a Phenotype-Based Genetic Test Prediction Score for Unrelated Patients With Hypertrophic Cardiomyopathy

Published on Jun 1, 2014
· DOI :10.1016/J.MAYOCP.2014.01.025
J. Martijn Bos32
Estimated H-index: 32
(Mayo Clinic),
Melissa L. Will26
Estimated H-index: 26
(Mayo Clinic)
+ 3 AuthorsMichael J. Ackerman144
Estimated H-index: 144
(Mayo Clinic)
Abstract Objectives To determine the prevalence and spectrum of mutations and genotype-phenotype relationships in the largest hypertrophic cardiomyopathy (HCM) cohort to date and to provide an easy, clinically applicable phenotype-derived score that provides a pretest probability for a positive HCM genetic test result. Patients and Methods Between April 1, 1997, and February 1, 2007, 1053 unrelated patients with the clinical diagnosis of HCM (60% male; mean ± SD age at diagnosis, 44.4±19 years) had HCM genetic testing for the 9 HCM-associated myofilament genes. Phenotyping was performed by review of electronic medical records. Results Overall, 359 patients (34%) were genotype positive for a putative HCM-associated mutation in 1 or more HCM-associated genes. Univariate and multivariate analyses identified the echocardiographic reverse curve morphological subtype, an age at diagnosis younger than 45 years, a maximum left ventricular wall thickness of 20 mm or greater, a family history of HCM, and a family history of sudden cardiac death as positive predictors of positive genetic test results, whereas hypertension was a negative predictor. A score, based on the number of predictors of a positive genetic test result, predicted a positive genetic test result ranging from 6% when only hypertension was present to 80% when all 5 positive predictor markers were present. Conclusion In this largest HCM cohort published to date, the overall yield of genetic testing was 34%. Although all the patients were diagnosed clinically as having HCM, the presence or absence of 6 simple clinical/echocardiographic markers predicted the likelihood of mutation-positive HCM. Phenotype-guided genetic testing using the Mayo HCM Genotype Predictor score provides an easy tool for an effective genetic counseling session.
📖 Papers frequently viewed together
2,262 Citations
14 Authors (Bernard J. Gersh, ..., Clyde W. Yancy)
651 Citations
14 Authors (Bernard J. Gersh, ..., Harry Rakowski)
1,877 Citations
#1Christiane Gruner (UHN: University Health Network)H-Index: 18
#2Joan IvanovH-Index: 77
Last. Harry RakowskiH-Index: 59
view all 10 authors...
Background— Genotyping in hypertrophic cardiomyopathy has gained increasing attention in the past decade. Its major role is for family screening and rarely influences decision-making processes in any individual patient. It is associated with substantial costs, and cost-effectiveness can only be achieved in the presence of high-detection rates for disease-causing sarcomere protein gene mutations. Therefore, our aim was to develop a score based on clinical and echocardiographic variables that allo...
69 CitationsSource
#1Feng Lan (Stanford University)H-Index: 27
#2Andrew S. Lee (Stanford University)H-Index: 38
Last. Joseph C. Wu (Stanford University)H-Index: 123
view all 24 authors...
Summary Familial hypertrophic cardiomyopathy (HCM) is a prevalent hereditary cardiac disorder linked to arrhythmia and sudden cardiac death. While the causes of HCM have been identified as genetic mutations in the cardiac sarcomere, the pathways by which sarcomeric mutations engender myocyte hypertrophy and electrophysiological abnormalities are not understood. To elucidate the mechanisms underlying HCM development, we generated patient-specific induced pluripotent stem cell cardiomyocytes (iPSC...
452 CitationsSource
#1Jodie Ingles (Centenary Institute)H-Index: 33
#2T. Sarina (Centenary Institute)H-Index: 5
Last. Christopher Semsarian (Centenary Institute)H-Index: 63
view all 10 authors...
Purpose: Genetic testing for hypertrophic cardiomyopathy has been commercially available for almost a decade; however, low mutation detection rate and cost have hindered uptake. This study sought to identify clinical variables that can predict probands with hypertrophic cardiomyopathy in whom a pathogenic mutation will be identified.
84 CitationsSource
#1Alexander G. Bick (MIT: Massachusetts Institute of Technology)H-Index: 28
#2Jason Flannick (MIT: Massachusetts Institute of Technology)H-Index: 39
Last. Christine E. Seidman (Harvard University)H-Index: 150
view all 24 authors...
Rare sarcomere protein variants cause dominant hypertrophic and dilated cardiomyopathies. To evaluate whether allelic variants in eight sarcomere genes are associated with cardiac morphology and function in the community, we sequenced 3,600 individuals from the Framingham Heart Study (FHS) and Jackson Heart Study (JHS) cohorts. Out of the total, 11.2% of individuals had one or more rare nonsynonymous sarcomere variants. The prevalence of likely pathogenic sarcomere variants was 0.6%, twice the p...
91 CitationsSource
#1Jessica R. Golbus (U of C: University of Chicago)H-Index: 9
#2Megan J. Puckelwartz (U of C: University of Chicago)H-Index: 17
Last. Elizabeth M. McNally (U of C: University of Chicago)H-Index: 82
view all 6 authors...
Background— Hypertrophic cardiomyopathy and dilated cardiomyopathy arise from mutations in genes encoding sarcomere proteins including MYH7 , MYBPC3 , and TTN . Genetic diagnosis of cardiomyopathy relies on complete sequencing of the gene coding regions, and most pathogenic variation is rare. The 1000 Genomes Project is an ongoing consortium designed to deliver whole genome sequence information from an ethnically diverse population and, therefore, is a rich source to determine both common and ra...
113 CitationsSource
#1Jodie Ingles (Centenary Institute)H-Index: 33
#2Laura Yeates (Centenary Institute)H-Index: 17
Last. Christopher Semsarian (Centenary Institute)H-Index: 63
view all 7 authors...
Genetic testing for inherited heart diseases: longitudinal impact on health-related quality of life
21 CitationsSource
Alice K. Jacobs, MD, FACC, FAHA, Chair, 2009–2011; Sidney C. Smith, Jr, MD, FACC, FAHA, Immediate Past Chair, 2006–2008[¶¶][1]; Jeffrey L. Anderson, MD, FACC, FAHA, Chair-Elect; Nancy M. Albert, PhD, CCNS, CCRN, FAHA; Christopher E. Buller, MD, FACC[¶¶][1]; Mark A. Creager, MD, FACC, FAHA;
962 CitationsSource
#1Bernard J. GershH-Index: 163
#2Barry J. MaronH-Index: 169
Last. Harry Rakowski (American Society of Echocardiography)H-Index: 9
view all 14 authors...
2011;58;2703-2738; originally published online Nov 8, 2011; J. Am. Coll. Cardiol. W. Yancy Rakowski, Christine E. Seidman, Jeffrey A. Towbin, James E. Udelson, and Clyde Fifer, Mark S. Link, Srihari S. Naidu, Rick A. Nishimura, Steve R. Ommen, Harry Bernard J. Gersh, Barry J. Maron, Robert O. Bonow, Joseph A. Dearani, Michael A. Thoracic Surgeons Society for Cardiovascular Angiography and Interventions, and Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, of...
1,877 CitationsSource
#1Jodie Ingles (Centenary Institute)H-Index: 33
#2Laura Yeates (Centenary Institute)H-Index: 17
Last. Christopher Semsarian (Centenary Institute)H-Index: 63
view all 3 authors...
s a f Major advances have been made in our understanding of the genetic basis of cardiac disease over the last 2 decades. These disorders encompass a range of cardiovascular diseases, from primary arrhythmogenic diseases and inherited cardiomyopathies to metabolic, vascular, and congenital heart diseases. The emergence of these genetic heart diseases has had a direct impact both on individuals with disease and on at-risk family members. This knowledge, coupled with major advances in genetic tech...
83 CitationsSource
#1Jodie Ingles (Centenary Institute)H-Index: 33
#2Poonam Zodgekar (VCCRI: Victor Chang Cardiac Research Institute)H-Index: 3
Last. Diane Fatkin (VCCRI: Victor Chang Cardiac Research Institute)H-Index: 55
view all 6 authors...
Inherited gene variants have been implicated increasingly in cardiac disorders but the clinical impact of these discoveries has been variable. For some disorders, such as familial hypertrophic cardiomyopathy, long QT syndrome, and familial hypercholesterolaemia, genetic testing has a high yield and has become an integral part of family management. For other disorders, including dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome, catecholaminergic polymorphi...
51 CitationsSource
Cited By97
Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with an estimated prevalence of up to 1 in 200 individuals. In the majority of cases, HCM is considered a Mendelian disease, with mainly autosomal dominant inheritance. Most pathogenic variants are usually detected in genes for sarcomeric proteins. Nowadays, the genetic basis of HCM is believed to be rather complex. Thousands of mutations in more than 60 genes have been described in association with HCM. Nevertheless, screenin...
#1Sae X. Morita (Columbia University)
#2Kenya Kusunose (University of Tokushima)H-Index: 27
Last. Yuichi J. Shimada (Columbia University)H-Index: 12
view all 10 authors...
Genetic testing provides valuable insights into family screening strategies, diagnosis, and prognosis in patients with hypertrophic cardiomyopathy (HCM). On the other hand, genetic testing carries socio-economical and psychological burdens. It is therefore important to identify patients with HCM who are more likely to have positive genotype. However, conventional prediction models based on clinical and echocardiographic parameters offer only modest accuracy and are subject to intra- and inter-ob...
#1Gherardo Finocchiaro ('KCL': King's College London)H-Index: 4
#2Nabeel Sheikh ('KCL': King's College London)H-Index: 16
Last. Iacopo OlivottoH-Index: 64
view all 12 authors...
Myocardial disarray is defined as disorganized cardiomyocyte spatial distribution, with loss of physiological fibre alignment and orientation. Since the first pathological descriptions of hypertrophic cardiomyopathy (HCM), disarray appeared as a typical feature of this condition and sparked vivid debate regarding its specificity to the disease and clinical significance as a diagnostic marker and a risk factor for sudden death. Although much of the controversy surrounding its diagnostic value in ...
2 CitationsSource
Hypertrophic cardiomyopathy (HCM) is the most common monogenic cardiac disease with a highly variable phenotypic expression, ranging from asymptomatic to drug refractory heart failure (HF) presentation. Pharmacological therapy is the first line of treatment, but options are currently limited to nonspecific medication like betablockers or calcium channel inhibitors, with frequent suboptimal results. While being the gold standard practice for the management of drug refractory HCM patients, septal ...
#1Xiaofei YangH-Index: 2
#2Zhenghao LiH-Index: 1
Last. Cuifen Zhao (SDU: Shandong University)H-Index: 3
view all 5 authors...
Objectives null This study aims to investigate the pathogenic gene variant in a family with hypertrophic cardiomyopathy by using whole-exome sequencing and to explore the relationship between the gene variant and clinical phenotype. null Methods null Peripheral blood was collected from a family with hypertrophic cardiomyopathy, and deoxyribonucleic acid was extracted. The possible pathogenic genes were detected by whole-exome sequencing, and the variant was verified by Sanger sequencing. Functio...
#1Mohamed Z Alimohamed (UMCG: University Medical Center Groningen)H-Index: 2
#2Lennart Johansson (UMCG: University Medical Center Groningen)H-Index: 15
Last. Paul A. van der Zwaag (UMCG: University Medical Center Groningen)H-Index: 16
view all 14 authors...
Abstract Background Next-generation sequencing (NGS) is increasingly used for clinical evaluation of cardiomyopathy patients as it allows for simultaneous screening of multiple cardiomyopathy-associated genes. Adding copy number variant (CNV) analysis of NGS data is not routine yet and may contribute to the diagnostic yield. Objectives Determine the diagnostic yield of our targeted NGS gene panel in routine clinical diagnostics of Dutch cardiomyopathy patients and explore the impact of exon CNVs...
#1Hongyu Zhou (CAS: Chinese Academy of Sciences)H-Index: 4
#2Lu Li (Peking Union Medical College)H-Index: 3
Last. Jie TianH-Index: 95
view all 11 authors...
The high variability of hypertrophic cardiomyopathy (HCM) genetic phenotypes has prompted the establishment of risk-stratification systems that predict the risk of a positive genetic mutation based on clinical and echocardiographic profiles. This study aims to improve mutation-risk prediction by extracting cardiovascular magnetic resonance (CMR) morphological features using a deep learning algorithm. We recruited 198 HCM patients (48% men, aged 47 ± 13 years) and divided them into training (147 ...
5 CitationsSource
#1Amir Aziz (U of A: University of Alberta)
#2Szymon K. Musiol (North Bristol NHS Trust)
Last. Gregory Y.H. Lip (University of Liverpool)H-Index: 195
view all 6 authors...
INTRODUCTION Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac condition and the most common cause of sudden cardiac death (SCD) in patients below the age of 35. Genetic testing is a vital part of HCM diagnostics, yet correlation with clinical phenotypes remains complex. Identifying clinical predictors of informative genetic testing may prevent unnecessary investigations and improve cost-effectiveness of services. This article reviews the current literature pertinent to iden...
1 CitationsSource
#1Lusha W Liang (Columbia University)
#2Michael A. Fifer (Harvard University)H-Index: 43
Last. Yuichi J. Shimada (Columbia University)H-Index: 12
view all 6 authors...
Background - Genetic testing can determine family screening strategies and has prognostic and diagnostic value in hypertrophic cardiomyopathy (HCM). However, it can also pose a significant psychosocial burden. Conventional scoring systems offer modest ability to predict genotype positivity. The aim of our study was to develop a novel prediction model for genotype positivity in patients with HCM by applying machine learning (ML) algorithms. Methods - We constructed three ML models using readily a...
2 CitationsSource
#1Julie Hathaway (Quest Diagnostics)H-Index: 1
#2Krista Heliö (UH: University of Helsinki)H-Index: 2
Last. Juha W. Koskenvuo (Quest Diagnostics)H-Index: 1
view all 21 authors...
BACKGROUND Genetic testing in hypertrophic cardiomyopathy (HCM) is a published guideline-based recommendation. The diagnostic yield of genetic testing and corresponding HCM-associated genes have been largely documented by single center studies and carefully selected patient cohorts. Our goal was to evaluate the diagnostic yield of genetic testing in a heterogeneous cohort of patients with a clinical suspicion of HCM, referred for genetic testing from multiple centers around the world. METHODS A ...
2 CitationsSource