Top

Journal of Cardiovascular Translational Research

Published in:

01-12-2009

A New Era in Clinical Genetic Testing for Hypertrophic Cardiomyopathy

Authors: Matthew Wheeler, Aleksandra Pavlovic, Emil DeGoma, Heidi Salisbury, Colleen Brown, Euan A. Ashley

Published in: Journal of Cardiovascular Translational Research | Issue 4/2009

Abstract

Building on seminal studies of the last 20 years, genetic testing for hypertrophic cardiomyopathy (HCM) has become a clinical reality in the form of targeted exonic sequencing of known disease-causing genes. This has been driven primarily by the decreasing cost of sequencing, but the high profile of genome-wide association studies, the launch of direct-to-consumer genetic testing, and new legislative protection have also played important roles. In the clinical management of hypertrophic cardiomyopathy, genetic testing is primarily used for family screening. An increasing role is recognized, however, in diagnostic settings: in the differential diagnosis of HCM; in the differentiation of HCM from hypertensive or athlete’s heart; and more rarely in preimplantation genetic diagnosis. Aside from diagnostic clarification and family screening, use of the genetic test for guiding therapy remains controversial, with data currently too limited to derive a reliable mutation risk prediction from within the phenotypic noise of different modifying genomes. Meanwhile, the power of genetic testing derives from the confidence with which a mutation can be called present or absent in a given individual. This confidence contrasts with our more limited ability to judge the significance of mutations for which co-segregation has not been demonstrated. These variants of “unknown” significance represent the greatest challenge to the wider adoption of genetic testing in HCM. Looking forward, next-generation sequencing technologies promise to revolutionize the current approach as whole genome sequencing will soon be available for the cost of today’s targeted panel. In summary, our future will be characterized not by lack of genetic information but by our ability to effectively parse it.

Jones, W. H. S. (1923). Hippocratic collection vol 1-8. Cambridge: Harvard University Press.

Bateson, W. (1902). Mendel’s principles of heredity, a defense. London: Cambridge University Press.

Mendel, G. (1901). Experiments in plant hybridizaton (English translation). Journal of the Royal Horticultural Society, 26, 1–32.

Kerem, B., Rommens, J. M., Buchanan, J. A., et al. (1989). Identification of the cystic fibrosis gene: genetic analysis. Science, 245(4922), 1073–1080.CrossRefPubMed

Curran, M. E., Splawski, I., Timothy, K. W., Vincent, G. M., Green, E. D., & Keating, M. T. (1995). A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell, 80(5), 795–803.CrossRefPubMed

Wang, Q., Shen, J., Splawski, I., et al. (1995). SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell, 80(5), 805–811.CrossRefPubMed

Geisterfer-Lowrance, A. A., Kass, S., Tanigawa, G., et al. (1990). A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell, 62(5), 999–1006.CrossRefPubMed

Burton, P. R., Clayton, D. G., Cardon, L. R., Craddock, N., Deloukas, P., Duncanson, A., et al. (2007). Genome-wide association study of 14, 000 cases of seven common diseases and 3, 000 shared controls. Nature, 447(7145), 661–678.CrossRef

Hudson, K., Javitt, G., Burke, W., & Byers, P. (2007). ASHG Statement* on direct-to-consumer genetic testing in the United States. Obstetrics and Gynecology, 110(6), 1392–1395.PubMed

10.

Altman, R. B. (2009). Direct-to-consumer genetic testing: failure is not an option. Clinical Pharmacology and Therapeutics, 86(1), 15–17.CrossRefPubMed

11.

Hershberger, R. E., Lindenfeld, J., Mestroni, L., Seidman, C. E., Taylor, M. R., & Towbin, J. A. (2009). Genetic evaluation of cardiomyopathy–a Heart Failure Society of America practice guideline. Journal of Cardiac Failure, 15(2), 83–97.CrossRefPubMed

12.

Marston, S., Copeland, O., Jacques, A., et al. (2009). Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. Circulation Research, 105(3), 219–222.CrossRefPubMed

13.

Seidman, J. G., & Seidman, C. (2001). The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell, 104(4), 557–567.CrossRefPubMed

14.

Bos, J. M., Towbin, J. A., & Ackerman, M. J. (2009). Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. Journal of the American College of Cardiology, 54(3), 201–211.CrossRefPubMed

15.

Frazer, K. A., Ballinger, D. G., Cox, D. R., et al. (2007). A second generation human haplotype map of over 3.1 million SNPs. Nature, 449(7164), 851–861.CrossRefPubMed

16.

International HapMap Consortium. (2005). A haplotype map of the human genome. Nature, 437(7063), 1299–1320.CrossRef

17.

International HapMap Consortium. (2003). The International HapMap Project. Nature, 426(6968), 789–796.CrossRef

18.

Lander, E. S., Linton, L. M., Birren, B., et al. (2001). Initial sequencing and analysis of the human genome. Nature, 409(6822), 860–921.CrossRefPubMed

19.

Venter, J. C., Adams, M. D., Myers, E. W., et al. (2001). The sequence of the human genome. Science, 291(5507), 1304–1351.CrossRefPubMed

20.

McCarthy, M. I., Abecasis, G. R., Cardon, L. R., et al. (2008). Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nature Reviews. Genetics, 9(5), 356–369.CrossRefPubMed

21.

Frazer, K. A., Murray, S. S., Schork, N. J., & Topol, E. J. (2009). Human genetic variation and its contribution to complex traits. Nature Reviews. Genetics, 10(4), 241–251.CrossRefPubMed

22.

Storey, J. D., & Tibshirani, R. (2003). Statistical significance for genomewide studies. Proceedings of the National Academy of Sciences of the United States of America, 100(16), 9440–9445.CrossRefPubMed

23.

Maron, B. J., McKenna, W. J., Danielson, G. K., et al. (2003). American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. Journal of the American College of Cardiology, 42(9), 1687–1713.CrossRefPubMed

24.

Maron, B. J., Spirito, P., Wesley, Y., & Arce, J. (1986). Development and progression of left ventricular hypertrophy in children with hypertrophic cardiomyopathy. New England Journal of Medicine, 315(10), 610–614.PubMed

25.

European Society of Human Genetics. (2009). Genetic testing in asymptomatic minors: Recommendations of the European Society of Human Genetics. European Journal of Human Genetics, 7(6), 720–721.

26.

Maron, B. J., Roberts, W. C., Arad, M., et al. (2009). Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy. Jama, 301(12), 1253–1259.CrossRefPubMed

27.

Arad, M., Maron, B. J., Gorham, J. M., et al. (2005). Glycogen storage diseases presenting as hypertrophic cardiomyopathy. New England Journal of Medicine, 352(4), 362–372.CrossRefPubMed

28.

Hamour, I. M., Lachmann, H. J., Goodman, H. J., et al. (2008). Heart transplantation for homozygous familial transthyretin (TTR) V122I cardiac amyloidosis. American Journal of Transplantation, 8(5), 1056–1059.CrossRefPubMed

29.

Dubrey, S. W., Burke, M. M., Khaghani, A., Hawkins, P. N., Yacoub, M. H., & Banner, N. R. (2001). Long term results of heart transplantation in patients with amyloid heart disease. Heart (British Cardiac Society)., 85(2), 202–207.

30.

Schiffmann, R., Kopp, J. B., Austin, H. A., 3rd, et al. (2001). Enzyme replacement therapy in Fabry disease: a randomized controlled trial. Jama, 285(21), 2743–2749.CrossRefPubMed

31.

Eng, C. M., Guffon, N., Wilcox, W. R., et al. (2001). Safety and efficacy of recombinant human alpha-galactosidase A–replacement therapy in Fabry's disease. New England Journal of Medicine, 345(1), 9–16.CrossRefPubMed

32.

Buja, L. M. (2009). Evaluation of recombinant alpha-galactosidase A therapy for amelioration of the cardiovascular manifestations of Fabry disease: an important role for endomyocardial biopsy. Circulation, 119(19), 2539–2541.CrossRefPubMed

33.

Goldenberg, I., Zareba, W., & Moss, A. J. (2008). Long QT Syndrome. Current Problems in Cardiology, 33(11), 629–694.CrossRefPubMed

34.

Roden, D. M. (2008). Clinical practice. Long-QT syndrome. New England Journal of Medicine, 358(2), 169–176.CrossRefPubMed

35.

Lehnart, S. E., Ackerman, M. J., Benson, D. W., Jr., et al. (2007). Inherited arrhythmias: a National Heart, Lung, and Blood Institute and Office of Rare Diseases workshop consensus report about the diagnosis, phenotyping, molecular mechanisms, and therapeutic approaches for primary cardiomyopathies of gene mutations affecting ion channel function. Circulation, 116(20), 2325–2345.CrossRefPubMed

36.

Watkins, H., McKenna, W. J., Thierfelder, L., et al. (1995). Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. New England Journal of Medicine, 332(16), 1058–1064.CrossRefPubMed

37.

Watkins, H., Rosenzweig, A., Hwang, D. S., et al. (1992). Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. New England Journal of Medicine, 326(17), 1108–1114.PubMedCrossRef

38.

Marian, A. J., Yu, Q. T., Workman, R., Greve, G., & Roberts, R. (1993). Angiotensin-converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death. Lancet, 342(8879), 1085–1086.CrossRefPubMed

39.

van der Merwe, L., Cloete, R., Revera, M., et al. (2008). Genetic variation in angiotensin-converting enzyme 2 gene is associated with extent of left ventricular hypertrophy in hypertrophic cardiomyopathy. Human Genetics, 124(1), 57–61.CrossRefPubMed

40.

Perkins, M. J., Van Driest, S. L., Ellsworth, E. G., et al. (2005). Gene-specific modifying effects of pro-LVH polymorphisms involving the renin-angiotensin-aldosterone system among 389 unrelated patients with hypertrophic cardiomyopathy. European Heart Journal, 26(22), 2457–2462.CrossRefPubMed

41.

Fermin, D., Barac, A., Lee, S., et al. (2008). Sex and age dimorphism of myocardial gene expression in nonischemic human heart failure. Circ Cardiov Genetics., 1, 117–125.CrossRef

42.

Lind, J. M., Chiu, C., Ingles, J., et al. (2008). Sex hormone receptor gene variation associated with phenotype in male hypertrophic cardiomyopathy patients. Journal of Molecular and Cellular Cardiology, 45(2), 217–222.CrossRefPubMed

43.

Maron, B. J., & Ho, C. Y. (2009). Hypertrophic cardiomyopathy without hypertrophy: an emerging pre-clinical subgroup composed of genetically affected family members. Jacc, 2(1), 65–68.PubMed

44.

Semsarian, C., Ahmad, I., Giewat, M., et al. (2002). The L-type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model. Journal of Clinical Investigation, 109(8), 1013–1020.PubMed

45.

Handyside, A. H., Kontogianni, E. H., Hardy, K., & Winston, R. M. (1990). Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification. Nature, 344(6268), 768–770.CrossRefPubMed

46.

PGDIS. (2008). Guidelines for good practice in PGD: programme requirements and laboratory quality assurance. Reproductive Biomedicine Online, 16(1), 134–147.

47.

Basille, C., Frydman, R., El Aly, A., et al. (2009). Preimplantation genetic diagnosis: state of the art. European Journal of Obstetrics, Gynecology, and Reproductive Biology, 145(1), 9–13.CrossRefPubMed

48.

Krahn, T. (2009). Preimplantation genetic diagnosis: does age of onset matter (anymore)? Medicine, Health Care and Philosophy, 12(2), 187–202.CrossRef

49.

McArthur, S. J., Leigh, D., Marshall, J. T., Gee, A. J., De Boer, K. A., & Jansen, R. P. (2008). Blastocyst trophectoderm biopsy and preimplantation genetic diagnosis for familial monogenic disorders and chromosomal translocations. Prenatal Diagnosis, 28(5), 434–442.CrossRefPubMed

50.

Richards, C. S., Bale, S., Bellissimo, D. B., et al. (2008). ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genetics in Medicine, 10(4), 294–300.CrossRefPubMed

51.

Sunyaev, S., Ramensky, V., Koch, I., Lathe, W., 3rd, Kondrashov, A. S., & Bork, P. (2001). Prediction of deleterious human alleles. Human Molecular Genetics, 10(6), 591–597.CrossRefPubMed

52.

Kumar, P., Henikoff, S., & Ng, P. C. (2009). Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nature protocols., 4(8), 1073–1081.CrossRefPubMed

53.

Sanger, F., Air, G. M., Barrell, B. G., et al. (1977). Nucleotide sequence of bacteriophage phi X174 DNA. Nature, 265(5596), 687–695.CrossRefPubMed

54.

Shendure, J., & Ji, H. (2008). Next-generation DNA sequencing. Nature Biotechnology, 26(10), 1135–1145.CrossRefPubMed

55.

Braslavsky, I., Hebert, B., Kartalov, E., & Quake, S. R. (2003). Sequence information can be obtained from single DNA molecules. Proceedings of the National Academy of Sciences of the United States of America, 100(7), 3960–3964.CrossRefPubMed

56.

Pushkarev, D., Neff, N. F., & Quake, S. R. (2009). Single-molecule sequencing of an individual human genome. Nature Biotechnology, 27(9), 847–852.CrossRefPubMed

57.

Eid, J., Fehr, A., Gray, J., et al. (2009). Real-time DNA sequencing from single polymerase molecules. Science, 323(5910), 133–138.CrossRefPubMed

58.

Kim, J. B., Porreca, G. J., Song, L., et al. (2007). Polony multiplex analysis of gene expression (PMAGE) in mouse hypertrophic cardiomyopathy. Science, 316(5830), 1481–1484.CrossRefPubMed

Title: A New Era in Clinical Genetic Testing for Hypertrophic Cardiomyopathy
Authors: Matthew Wheeler
Aleksandra Pavlovic
Emil DeGoma
Heidi Salisbury
Colleen Brown
Euan A. Ashley
Publication date: 01-12-2009
Publisher: Springer US
Published in: Journal of Cardiovascular Translational Research / Issue 4/2009
Print ISSN: 1937-5387
Electronic ISSN: 1937-5395
DOI: https://doi.org/10.1007/s12265-009-9139-0

2024 ASCO Annual Meeting

Springer Medicine

A New Era in Clinical Genetic Testing for Hypertrophic Cardiomyopathy

Abstract

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2009

A Good Idea: A Physician’s Perspective on Genetic Counseling for Hypertrophic Cardiomyopathy

Experimental Therapies in Hypertrophic Cardiomyopathy

Role of Animal Models in HCM Research

Hypertrophic Cardiomyopathy at 50

Insights into Human β-Cardiac Myosin Function from Single Molecule and Single Cell Studies

Genetic Counseling and Testing for Hypertrophic Cardiomyopathy: the Pediatric Perspective