Genetic Screening of Hypertrophic Cardiomyopathy: Comparison
Please note this is a comparison between Version 3 by Conner Chen and Version 2 by Conner Chen.

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. 

  • hypertrophic cardiomyopathy
  • genetics
  • molecular genetic testing

1. Introduction

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder, defined by the presence of increased left ventricular (LV) wall thickness that is not solely explained by abnormal loading conditions [1][2]. In the majority of cases, HCM is considered a Mendelian disease with autosomal dominant inheritance, incomplete penetrance, and variable expressivity [3]. It is one of the most frequent inherited heart diseases with an estimated prevalence of up to 1 in 200 individuals and together with arrhythmogenic right ventricular cardiomyopathy (ARVC) among the most common cause of sudden cardiac death (SCD) in young athletes [4][5][6], who are often unaware of their underlying condition.

2. History of Finding the Cause of HCM

HCM was first described more than 60 years ago as asymmetrical myocardial hypertrophy with an increased risk of sudden cardiac death [7]. Although considered familial disease, the exact cause of HCM remained unknown for two subsequent decades.

Genetic studies in the 1980s and 1990s led to landmark discoveries that sarcomeric mutations cause both hypertrophic and dilated cardiomyopathies (DCM). In 1989, a mutation in the beta-myosin heavy chain (MYH7) gene was first identified as responsible for causing HCM [8][9]. During the next decade, numerous genes were reported to be associated with disease (Table 1) [10]. These eight sarcomeric genes (ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNI3, TNNT2, and TPM1) are commonly called core genes, with the most robust evidence to be causative of HCM (Table 1) [10][11]. This spectrum of sarcomeric genes has been gradually extended to non-sarcomeric genes encoding, for example, desmosomal proteins or ion channels [12][13]. However, a systematic evaluation of the investigation panels shows that the strongest evidence of causality remains in the eight core genes [11]. There is also strong evidence of causality in three genes—PLN, FLNC [11][14][15], and recently ALPK3 [16] and moderate evidence of causality in five genes—CSRP3, TNNC1, ACTN2JPH2, and FHOD3 [17][18]. For the other genes, evidence is weak or almost non-existent [11][13][19]. Variants in genes encoding non-sarcomeric proteins account for a small percentage of patients with HCM. In light of recently published analyses, they seem to be the presumed causal genes at several genome-wide association study loci [17][20], and their role in cardiomyopathy genetics is gradually expanding. Currently published data demonstrate that common genetic variants and modifiable risk factors have important roles in the HCM phenotype [17].

Table 1. Main sarcomeric genes associated with HCM.

Gene Protein Year of Discovery Frequency (%) * Inheritance Most Common

Pathogenic Variant

[22][23][24]. The Online Mendelian Inheritance in Man (OMIM) database currently lists 26 associated genes [25]. However, associations in at least 33 genes have already been reported [11] and 67 candidate genes are part of investigation panels at some expert sites [14].

It is clear, that genetic studies continue to demonstrate that HCM is predominantly a disease of the sarcomere, although the genetic basis of HCM is more diverse. Additionally, sarcomere mutations have been identified in association with other disorders of cardiac structure and function, apart from the above-mentioned DCM including restrictive cardiomyopathy and left ventricular non-compaction [26][27][28]. Moreover, recently published data suggest that shared genetic pathways contribute to HCM and DCM development with opposite directions of effect [20].

Genetic testing was initially possible only in research laboratories capable of performing linkage analysis and candidate gene sequencing in large, well-characterized families with obviously inherited diseases. The genetic and allelic heterogeneity of HCM makes molecular analysis by conventional methods time consuming and expensive [29][30]. Advances in contemporary DNA-sequencing methodology have made gene-based diagnosis increasingly feasible in routine clinical practice. Next-generation sequencing (NGS)-based genomic testing allows rapid analysis of a large number of genes or even a whole genome at similar cost and accuracy to conventional sequencing methods [30][31]. NGS is a high-throughput method that, in comparison with classical sequencing methods (Sanger), evaluates a large amount of genetic material quickly and is cheaper. NGS uses the principle of parallelization of the sequencing process, allowing the sequencing of thousands to millions of sequences simultaneously. In addition to classical examinations of genetic variability, mutation analysis of specific genes, and quantification of individual alleles, it is possible to examine the whole exome (WES) or to perform whole-genome sequencing (WGS).

Faster and more affordable genetic testing provides opportunities to improve diagnostic certainty when evaluating patients and families with relatively non-specific phenotypes of cardiac hypertrophy. With a molecular-level diagnosis, we can differentiate genetic sarcomeric HCM from phenocopies, such as hypertensive heart disease, athlete’s heart, and storage or metabolic disorders [32][33][34][35][36].

Nevertheless, screening large numbers of genes results in the identification of many genetic variants of uncertain significance (VUS) [30][31] and makes the interpretation of the results more difficult. The results of NGS produce a huge amount of output data with the subsequent need to sort and further analyze.

3. Identification of a Causative Mutation

For the clinical use of molecular genetic testing, the classification of the identified variants is essential. Due to a large amount of output data, a combined approach is currently used, based on the following rules:

-Frequency of variants in the control population, using international databases (e.g., 1000Genomes Project, Exome Sequencing Project, Exome Aggregation Consortium) [37][38][39]
-Published disease-associated variants (e.g., ClinVar, Human Gene Mutation Database) [40][41]
-In silico classification using software (e.g., Polyphen2, Sorting Intolerant From Tolerant) predicting the possible impact of the mutation on the structure and function of the final protein
-Mutations in the so-called evolutionarily highly conserved functional domains of the target protein
-Segregation analyses of genotype with phenotype in affected families (strong evidence)
-Functional studies on animal models or in vitro (expensive, complex)

In 2015, recommendations for the classification of genetic variants were published by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) [42], which is based on the above-listed principles. This classification divides the found variants into five following classes: (1) benign, (2) likely benign, (3) VUS—variant of unknown significance, (4) likely pathogenic (LP), and (5) pathogenic (P).

4. Genetic Screening

Genetic screening plays an important role in the management of patients with HCM and their relatives. The standard procedure is to obtain a detailed family history (at least three generations) and molecular genetic examination of the proband with a focus on at least all eight „core” sarcomeric genes associated with HCM (Table 1). If there is a clinical suspicion of a specific cause or HCM within the complex syndrome, then it is appropriate to expand the panel to other non-sarcomeric genes (Table 2).

Table 2. Non-sarcomeric genes associated with HCM.

Gene Protein Phenotype Prevalence * Inheritance Frequency (%) **
  Thick filament        
PRKAG2 Protein kinase, AMP-activated, gamma 2 subunit Wolff–Parkinson–White syndrome 1/4000 AD 0.2–1.0
MYH7 Beta-myosin heavy chain 1989 20–30 AD c.1988G>A
LAMP2 Protein kinase, AMP-activated, gamma 2 subunit Danon disease 1/100,000 X 0.1–0.2 MYL2 Regulatory myosin light chain 1998 2–4 AD c.173G>A
GLA Galactosidase, alpha Fabry disease 1/40,000 X 0.5–1.0 Essential myosin light chain 1996 1–2 AD
Four and a half LIM domains 1 Emery–Dreifuss myopathy 1/100,000 X 0.1–0.5   Thin filament        
TTR Transthyretin Amyloidosis *** 1/100,000 AD 0.8–5 TNNT2 Cardiac troponin T 1993 10 AD c.236T>A
GAA Glucosidase, alpha Pompe disease 1/40,000 AR 0.01–0.1 TNNI3 Cardiac troponin I 1997 7 AD c.433C>T
PTPN11 Protein tyrosine phosphatase, non-receptor type 11 Noonan syndrome

1/2000 AD 1–5 TPM1 Alpha tropomyosin 1993 <1 AD c.574G>A
FXN Frataxin Friedreich ataxiaACTC1 Alpha cardiac actin 1999 <1 AD c.301G>A
  Intermediate filament        
MYBPC3 Myosin-binding protein C 1993 30–40 AD c.1504C>T

AD—autosomal dominant, * Indicates relative frequency in HCM population.

Nowadays, more than 30 years after the publication of the first causal mutation in the MYH7 gene, thousands of mutations have been described and the numbers of identified HCM-associated genes are gradually increasing [21]


AR—autosomal recessive, X-X linked, * Indicates prevalence in the general population, ** Indicates relative frequency among HCM cases, may differ from the expected prevalence in the general population due to the selection bias of HCM genotyped cohorts, *** hereditary, not wild-type (senile).

In the case of a positive finding, molecular genetic testing of the first-degree relative for a specific gene and mutation already found in the proband is performed. If a pathogenic mutation is detected in a relative, a cascade examination of other relatives is possible (due to the predominant AD inheritance). Detailed family history and pedigree will help us to identify the probable hereditary cause of the disease and usually determine the type of heredity. Genetic analysis of post-mortem tissue samples with cascade screening of relatives is feasible [43]. The main clinical advantage is the situation where a specific causal mutation in the proband is not found in the first-degree relative. The relative can then be excluded from the dispensary, the probability of the disease is low, however, de novo mutations are possible. Therefore, we always warn patients about the need to seek a specialist in case of symptomatology. According to current recommendations, the examination of children is appropriate around the age of 6–10 [1][44]. The threshold was established based on pediatric studies, which showed a rare incidence of serious complications of HCM before the onset of puberty [45][46].

If the molecular genetic examination of the proband is negative (no P/LP variant is found), we continue the established regular clinical monitoring of first-degree relatives. It includes clinical and echocardiographic examination, 12-lead ECG, Holter ECG monitoring (Figure 1). In selected patients (usually with insufficient echocardiographic window), cardiac magnetic resonance imaging (MRI) is performed. MRI can be useful in young patients with an early-onset screening of metabolic diseases [44][47] and its role in SCD risk stratification is increasing [44][48].

Figure 1. Cascade genetic testing. B/LB—benign or likely benign, P/LP—pathogenic or likely pathogenic, VUS—variant of unknown significance, WES—whole exome sequencing, WGS—whole genome sequencing, ECG—electrocardiography, MRI—magnetic resonance imaging.

The opposite clinical situation is a clinically negative phenotype (F-) with the finding of P/LP mutation (genotype positive, G+). In contrast to DCM, where, for example, a mutation in the LMNA gene is associated with an unfavorable prognosis and is even part of the indication for ICD (implantable cardioverter-defibrillator) implantation according to ESC guidelines [49], the risk of SCD is generally low in individuals without expressed hypertrophy. Mutations in TNNT2 may be an exception, as suggested by some publications [50][51], but this is not strong evidence. It is not clear whether to make specific recommendations and propose restrictions, e.g., for professional athletes [21][52][53], based on a positive genotype without an expressed phenotype (G+/F-). It has been repeatedly reported that most G+/F- patients probably have a favorable prognosis [52][54]. However, due to age-related variable penetrance (55% to 30 years of age, up to 95% over 50 years of age [55], regular clinical monitoring of these individuals should be continued.


  1. Elliott, P.M.; Anastasakis, A.; Borger, M.; Borggrefe, M.; Cecchi, F.; Charron, P.; Hagege, A.; Lafont, A.; Limongelli, G.; Mahrholdt, H.; et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy. Eur. Heart J. 2014, 35, 2733–2779.
  2. Veselka, J.; Anavekar, N.S.; Charron, P. Hypertrophic obstructive cardiomyopathy. Lancet 2016, 389, 1253–1267.
  3. Richard, P.; Charron, P.; Carrier, L.; Ledeuil, C.; Cheav, T.; Pichereau, C.; Benaiche, A.; Isnard, R.; Dubourg, O.; Burban, M.; et al. Hypertrophic Cardiomyopathy. Circulation 2003, 107, 2227–2232.
  4. Maron, B.J.; Doerer, J.J.; Haas, T.S.; Tierney, D.; Mueller, F.O. Sudden Deaths in Young Competitive Athletes. Circulation 2009, 119, 1085–1092.
  5. Semsarian, C.; Ingles, J.; Maron, M.S.; Maron, B.J. New Perspectives on the Prevalence of Hypertrophic Cardiomyopathy. J. Am. Coll. Cardiol. 2015, 65, 1249–1254.
  6. Ackerman, M.; Atkins, D.L.; Triedman, J.K. Sudden Cardiac Death in the Young. Circulation 2016, 133, 1006–1026.
  7. Teare, D. Asymmetrical Hypertrophy of the Heart in Young Adults. Heart 1958, 20, 1–8.
  8. Geisterfer-Lowrance, A.A.; Kass, S.; Tanigawa, G.; Vosberg, H.-P.; McKenna, W.; Seidman, C.E.; Seidman, J. A molecular basis for familial hypertrophic cardiomyopathy: A β cardiac myosin heavy chain gene missense mutation. Cell 1990, 62, 999–1006.
  9. Jarcho, J.A.; McKenna, W.J.; Pare, J.P.; Solomon, S.D.; Holcombe, R.F.; Dickie, S.; Levi, T.; Donis-Keller, H.; Seidman, J.; Seidman, C.E. Mapping a Gene for Familial Hypertrophic Cardiomyopathy to Chromosome 14q1. N. Engl. J. Med. 1989, 321, 1372–1378.
  10. Ho, C.Y.; Charron, P.; Richard, P.; Girolami, F.; Van Spaendonck-Zwarts, K.Y.; Pinto, Y. Genetic advances in sarcomeric cardiomyopathies: State of the art. Cardiovasc. Res. 2015, 105, 397–408.
  11. Ingles, J.; Goldstein, J.; Thaxton, C.; Caleshu, C.; Corty, E.W.; Crowley, S.B.; Dougherty, K.; Harrison, S.M.; McGlaughon, J.; Milko, L.V.; et al. Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes. Circ. Genom. Precis. Med. 2019, 12, e002460.
  12. Lopes, L.; Syrris, P.; Guttmann, O.P.; O’Mahony, C.; Tang, H.C.; Dalageorgou, C.; Jenkins, S.; Hubank, M.; Monserrat, L.; McKenna, W.J.; et al. Novel genotype–phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. Heart 2014, 101, 294–301.
  13. Walsh, R.; Buchan, R.; Wilk, A.; John, S.; Felkin, L.E.; Thomson, K.; Chiaw, T.H.; Loong, C.C.W.; Pua, C.J.; Raphael, C.; et al. Defining the genetic architecture of hypertrophic cardiomyopathy: Re-evaluating the role of non-sarcomeric genes. Eur. Heart J. 2017, 38, 3461–3468.
  14. Thomson, K.L.; NIHR BioResource—Rare Diseases Consortium; Ormondroyd, E.; Harper, A.R.; Dent, T.; McGuire, K.; Baksi, J.; Blair, E.; Brennan, P.; Buchan, R.; et al. Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield. Genet. Med. 2018, 21, 1576–1584.
  15. Mazzarotto, F.; Olivotto, I.; Boschi, B.; Girolami, F.; Poggesi, C.; Barton, P.; Walsh, R. Contemporary Insights Into the Genetics of Hypertrophic Cardiomyopathy: Toward a New Era in Clinical Testing? J. Am. Heart Assoc. 2020, 9, e015473.
  16. Lopes, L.R.; Garcia-Hernández, S.; Lorenzini, M.; Futema, M.; Chumakova, O.; Zateyshchikov, D.; Isidoro-Garcia, M.; Villacorta, E.; Escobar-Lopez, L.; Garcia-Pavia, P.; et al. Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy. Eur. Heart J. 2021, 42, 3063–3073.
  17. Harper, A.R.; HCMR Investigators; Goel, A.; Grace, C.; Thomson, K.L.; Petersen, S.E.; Xu, X.; Waring, A.; Ormondroyd, E.; Kramer, C.M.; et al. Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. Nat. Genet. 2021, 53, 135–142.
  18. Ochoa, J.P.; Sabater-Molina, M.; García-Pinilla, J.M.; Mogensen, J.; Restrepo-Córdoba, A.; Palomino-Doza, J.; Villacorta, E.; Martinez-Moreno, M.; Ramos-Maqueda, J.; Zorio, E.; et al. Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy. J. Am. Coll. Cardiol. 2018, 72, 2457–2467.
  19. Walsh, R.; Offerhaus, J.A.; Tadros, R.; Bezzina, C.R. Minor hypertrophic cardiomyopathy genes, major insights into the genetics of cardiomyopathies. Nat. Rev. Cardiol. 2021.
  20. Tadros, R.; Francis, C.; Xu, X.; Vermeer, A.M.C.; Harper, A.R.; Huurman, R.; Bisabu, K.K.; Walsh, R.; Hoorntje, E.T.; Rijdt, W.P.T.; et al. Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect. Nat. Genet. 2021, 53, 128–134.
  21. Maron, B.J.; Maron, M.S.; Semsarian, C. Genetics of Hypertrophic Cardiomyopathy After 20 Years. J. Am. Coll. Cardiol. 2012, 60, 705–715.
  22. Alfares, A.A.; Kelly, M.A.; McDermott, G.; Funke, B.H.; Lebo, M.S.; Baxter, S.B.; Shen, J.; McLaughlin, H.M.; Clark, E.H.; Babb, L.J.; et al. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: Expanded panels offer limited additional sensitivity. Genet. Med. 2015, 17, 880–888.
  23. Ingles, J.; Burns, C.; Barratt, A.; Semsarian, C. Application of Genetic Testing in Hypertrophic Cardiomyopathy for Preclinical Disease Detection. Circ. Cardiovasc. Genet. 2015, 8, 852–859.
  24. Sabater-Molina, M.; Pérez-Sánchez, I.; Del Rincón, J.H.; Gimeno, J. Genetics of hypertrophic cardiomyopathy: A review of current state. Clin. Genet. 2017, 93, 3–14.
  25. Online Mendelian Inheritance in Man. Available online: (accessed on 28 August 2021).
  26. McNally, E.; Dellefave, L. Sarcomere Mutations in Cardiogenesis and Ventricular Noncompaction. Trends Cardiovasc. Med. 2009, 19, 17–21.
  27. Mogensen, J.; Kubo, T.; Duque, M.; Uribe, W.; Shaw, A.; Murphy, R.; Gimeno, J.R.; Elliott, P.; McKenna, W.J. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J. Clin. Investig. 2003, 111, 209–216.
  28. Cimiotti, D.; Budde, H.; Hassoun, R.; Jaquet, K. Genetic Restrictive Cardiomyopathy: Causes and Consequences—An Integrative Approach. Int. J. Mol. Sci. 2021, 22, 558.
  29. Bortot, B.; Athanasakis, E.; Brun, F.; Rizzotti, D.; Mestroni, L.; Sinagra, G.; Severini, G.M. High-throughput Genotyping Robot-assisted Method for Mutation Detection in Patients With Hypertrophic Cardiomyopathy. Diagn. Mol. Pathol. 2011, 20, 175–179.
  30. Fokstuen, S.; Munoz, A.; Melacini, P.; Iliceto, S.; Perrot, A.; Ozcelik, C.; Jeanrenaud, X.; Rieubland, C.; Farr, M.; Faber, L.; et al. Rapid detection of genetic variants in hypertrophic cardiomyopathy by custom DNA resequencing array in clinical practice. J. Med. Genet. 2011, 48, 572–576.
  31. Meder, B.; Haas, J.; Keller, A.; Heid, C.; Just, S.; Borries, A.; Boisguerin, V.; Scharfenberger-Schmeer, M.; Stähler, P.; Beier, M.; et al. Targeted Next-Generation Sequencing for the Molecular Genetic Diagnostics of Cardiomyopathies. Circ. Cardiovasc. Genet. 2011, 4, 110–122.
  32. Charron, P.; Villard, E.; Sébillon, P.; Laforêt, P.; Maisonobe, T.; Duboscq-Bidot, L.; Romero, N.; Drouin-Garraud, V.; Frébourg, T.; Richard, P.; et al. Danon’s disease as a cause of hypertrophic cardiomyopathy: A systematic survey. Heart 2004, 90, 842–846.
  33. Bernstein, H.S.; Bishop, D.F.; Astrin, K.H.; Kornreich, R.; Eng, C.M.; Sakuraba, H.; Desnick, R.J. Fabry disease: Six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene. J. Clin. Investig. 1989, 83, 1390–1399.
  34. Martiniuk, F.; Mehler, M.; Bodkin, M.; Tzall, S.; Hirschhorn, K.; Zhong, N.; Hirschhorn, R. Identification of a Missense Mutation in an Adult-Onset Patient with Glycogenosis Type II Expressing Only One Allele. DNA Cell Biol. 1991, 10, 681–687.
  35. Martiniuk, F.; Mehler, M.; Pellicer, A.; Tzall, S.; La Badie, G.; Hobart, C.; Ellenbogen, A.; Hirschhorn, R. Isolation of a cDNA for human acid alpha-glucosidase and detection of genetic heterogeneity for mRNA in three alpha-glucosidase-deficient patients. Proc. Natl. Acad. Sci. USA 1986, 83, 9641–9644.
  36. Van der Ploeg, A.T.; Hoefsloot, L.H.; Hoogeveen-Westerveld, M.; Petersen, E.M.; Reuser, A.J. Glycogenosis type II: Protein and DNA analysis in five South African families from various ethnic origins. Am. J. Hum. Gen. 1989, 44, 787–793.
  37. Genomes Project. Available online: (accessed on 28 August 2021).
  38. Exome Aggregation Consortium. Available online: (accessed on 28 August 2021).
  39. Exome Sequencing Project. Available online: (accessed on 28 August 2021).
  40. ClinVar. Available online: (accessed on 28 August 2021).
  41. Human Gene Mutation Database. Available online: (accessed on 28 August 2021).
  42. Richards, S.; Aziz, N.; Bale, S.; Bick, D.; Das, S.; Gastier-Foster, J.; Grody, W.W.; Hegde, M.; Lyon, E.; Spector, E.; et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 2015, 17, 405–423.
  43. Lahrouchi, N.; Raju, H.; Lodder, E.M.; Papatheodorou, E.; Miles, C.; Ware, J.S.; Papadakis, M.; Tadros, R.; Cole, D.; Skinner, J.R.; et al. The yield of postmortem genetic testing in sudden death cases with structural findings at autopsy. Eur. J. Hum. Genet. 2019, 28, 17–22.
  44. Writing Committee Members; Ommen, S.R.; Mital, S.; Burke, M.A.; Day, S.M.; Deswal, A.; Elliott, P.; Evanovich, L.L.; Hung, J.; Joglar, J.A.; et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients with Hypertrophic Cardiomyopathy. Circulation 2020, 142.
  45. Cardoso, B.; Gomes, I.; Loureiro, P.; Trigo, C.; Pinto, F.F. Diagnóstico clínico e genético de miocardiopatia hipertrófica familiar: Resultados em cardiologia pediátrica. Rev. Port. Cardiol. 2017, 36, 155–165.
  46. Jensen, M.K.; Havndrup, O.; Christiansen, M.; Andersen, P.S.; Diness, B.; Axelsson, A.; Skovby, F.; Køber, L.; Bundgaard, H. Penetrance of Hypertrophic Cardiomyopathy in Children and Adolescents. Circulation 2013, 127, 48–54.
  47. Hershberger, R.E.; Givertz, M.M.; Ho, C.Y.; Judge, D.; Kantor, P.F.; McBride, K.L.; Morales, A.; Taylor, M.R.; Vatta, M.; Ware, S.M. Genetic Evaluation of Cardiomyopathy—A Heart Failure Society of America Practice Guideline. J. Card. Fail. 2018, 24, 281–302.
  48. Moore, B.; Semsarian, C.; Chan, K.H.; Sy, R.W. Sudden Cardiac Death and Ventricular Arrhythmias in Hypertrophic Cardiomyopathy. Heart Lung Circ. 2018, 28, 146–154.
  49. Priori, S.G.; Blomström-Lundqvist, C.; Mazzanti, A.; Blom, N.; Borggrefe, M.; Camm, J.; Elliott, P.; Fitzsimons, D.; Hatala, R.; Hindricks, G.; et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Europace 2015, 17, 1601–1687.
  50. Olivotto, I.; Girolami, F.; Ackerman, M.J.; Nistri, S.; Bos, J.M.; Zachara, E.; Ommen, S.R.; Theis, J.L.; Vaubel, R.A.; Re, F.; et al. Myofilament Protein Gene Mutation Screening and Outcome of Patients With Hypertrophic Cardiomyopathy. Mayo Clin. Proc. 2008, 83, 630–638.
  51. Varnava, A.M.; Elliott, P.M.; Baboonian, C.; Davison, F.; Davies, M.J.; McKenna, W.J. Hypertrophic Cardiomyopathy. Circulation 2001, 104, 1380–1384.
  52. Maron, B.J.; Yeates, L.; Semsarian, C. Clinical Challenges of Genotype Positive (+)–Phenotype Negative (−) Family Members in Hypertrophic Cardiomyopathy. Am. J. Cardiol. 2011, 107, 604–608.
  53. Ho, C.Y. Genetics and Clinical Destiny: Improving Care in Hypertrophic Cardiomyopathy. Circulation 2010, 122, 2430–2440.
  54. Maurizi, N.; Michels, M.; Rowin, E.J.; Semsarian, C.; Girolami, F.; Tomberli, B.; Cecchi, F.; Maron, M.S.; Olivotto, I.; Maron, B.J. Clinical Course and Significance of Hypertrophic Cardiomyopathy Without Left Ventricular Hypertrophy. Circulation 2019, 139, 830–833.
  55. Charron, P.; Carrier, L.; Dubourg, O.; Tesson, F.; Desnos, M.; Richard, P.; Bonne, G.; Guicheney, P.; Hainque, B.; Bouhour, J.B.; et al. Penetrance of familial hypertrophic cardiomyopathy. Genet. Couns. 1997, 8, 107–114.
Video Production Service