Genetic Analysis of Familial Hypertrophic Cardiomyopathy

To map the genetic defect responsible for familial hypertrophic cardiomyopathy.

Study Overview

• Status: Completed
• Conditions: Heart Diseases; Cardiovascular Diseases; Cardiomyopathy, Hypertrophic; Myocardial Diseases

Detailed Description

BACKGROUND:

Familial hypertrophic cardiomyopathy is a disease of heart muscle that is genetically transmitted as an autosomal dominant trait, with a high degree of penetrance. Affected individuals typically have asymmetric thickening of the interventricular septum often involving the adjacent left ventricular free wall. Histologically, myocardial cells are enlarged and muscle bundles are grossly disorganized, producing a whorled pattern. The physiologic consequence of this cardiomyopathy is diastolic dysfunction with impaired ventricular relaxation and elevated diastolic pressures in the heart and pulmonary vasculature. Patients can experience dyspnea, angina, palpitations, and syncope. Complications of the disease include atrial fibrillation, congestive heart failure, thromboembolism, and most importantly, sudden death.

DESIGN NARRATIVE:

The three kindreds studied included one in Iceland, one in the St. Lawrence region in Canada, and one in the Pittsburgh, Pennsylvania area. Pedigrees were established for the three kindreds. All family members were clinically evaluated by physical exam, electrocardiogram, and comprehensive M-mode and two-dimensional echocardiography. Lymphoblastoid cell lines were derived from all members of the three pedigrees. Restriction fragment length polymorphism analyses were used to identify a DNA probe that was linked to familial hypertrophic cardiomyopathy. Studies were conducted to determine if the familial hypertrophic cardiomyopathy locus was the same in all three kindreds and to identify the gene responsible.

The study completion date listed in this record was obtained from the "End Date" entered in the Protocol Registration and Results System (PRS) record.

• Study Type: Observational

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 100 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

No eligibility criteria

Study Plan

How is the study designed?

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

General Publications

• Watkins H, Thierfelder L, Hwang DS, McKenna W, Seidman JG, Seidman CE. Sporadic hypertrophic cardiomyopathy due to de novo myosin mutations. J Clin Invest. 1992 Nov;90(5):1666-71. doi: 10.1172/JCI116038.
• Watkins H, Seidman CE, MacRae C, Seidman JG, McKenna W. Progress in familial hypertrophic cardiomyopathy: molecular genetic analyses in the original family studied by Teare. Br Heart J. 1992 Jan;67(1):34-8. doi: 10.1136/hrt.67.1.34. No abstract available.
• Seidman CE, Seidman JG. Mutations in cardiac myosin heavy chain genes cause familial hypertrophic cardiomyopathy. Mol Biol Med. 1991 Apr;8(2):159-66.
• Solomon SD, Jarcho JA, McKenna W, Geisterfer-Lowrance A, Germain R, Salerni R, Seidman JG, Seidman CE. Familial hypertrophic cardiomyopathy is a genetically heterogeneous disease. J Clin Invest. 1990 Sep;86(3):993-9. doi: 10.1172/JCI114802.
• Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell. 1990 Sep 7;62(5):999-1006. doi: 10.1016/0092-8674(90)90274-i.
• Solomon SD, Geisterfer-Lowrance AA, Vosberg HP, Hiller G, Jarcho JA, Morton CC, McBride WO, Mitchell AL, Bale AE, McKenna WJ, et al. A locus for familial hypertrophic cardiomyopathy is closely linked to the cardiac myosin heavy chain genes, CRI-L436, and CRI-L329 on chromosome 14 at q11-q12. Am J Hum Genet. 1990 Sep;47(3):389-94.
• Tanigawa G, Jarcho JA, Kass S, Solomon SD, Vosberg HP, Seidman JG, Seidman CE. A molecular basis for familial hypertrophic cardiomyopathy: an alpha/beta cardiac myosin heavy chain hybrid gene. Cell. 1990 Sep 7;62(5):991-8. doi: 10.1016/0092-8674(90)90273-h.
• Knowlton KU, Rockman HA, Itani M, Vovan A, Seidman CE, Chien KR. Divergent pathways mediate the induction of ANF transgenes in neonatal and hypertrophic ventricular myocardium. J Clin Invest. 1995 Sep;96(3):1311-8. doi: 10.1172/JCI118166.
• Watkins H, MacRae C, Thierfelder L, Chou YH, Frenneaux M, McKenna W, Seidman JG, Seidman CE. A disease locus for familial hypertrophic cardiomyopathy maps to chromosome 1q3. Nat Genet. 1993 Apr;3(4):333-7. doi: 10.1038/ng0493-333.
• Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg HP, Seidman JG, Seidman CE. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell. 1994 Jun 3;77(5):701-12. doi: 10.1016/0092-8674(94)90054-x.
• Anan R, Greve G, Thierfelder L, Watkins H, McKenna WJ, Solomon S, Vecchio C, Shono H, Nakao S, Tanaka H, et al. Prognostic implications of novel beta cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy. J Clin Invest. 1994 Jan;93(1):280-5. doi: 10.1172/JCI116957.
• Watkins H, Thierfelder L, Anan R, Jarcho J, Matsumori A, McKenna W, Seidman JG, Seidman CE. Independent origin of identical beta cardiac myosin heavy-chain mutations in hypertrophic cardiomyopathy. Am J Hum Genet. 1993 Dec;53(6):1180-5.
• Solomon SD, Wolff S, Watkins H, Ridker PM, Come P, McKenna WJ, Seidman CE, Lee RT. Left ventricular hypertrophy and morphology in familial hypertrophic cardiomyopathy associated with mutations of the beta-myosin heavy chain gene. J Am Coll Cardiol. 1993 Aug;22(2):498-505. doi: 10.1016/0735-1097(93)90055-6.
• Watkins H, Rosenzweig A, Hwang DS, Levi T, McKenna W, Seidman CE, Seidman JG. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med. 1992 Apr 23;326(17):1108-14. doi: 10.1056/NEJM199204233261703.

Study record dates

Study Major Dates

• Study Start: January 1, 1990
• Study Completion (Actual): March 1, 1995

Study Registration Dates

• First Submitted: May 25, 2000
• First Submitted That Met QC Criteria: May 25, 2000
• First Posted (Estimate): May 26, 2000

Study Record Updates

• Last Update Posted (Estimate): March 16, 2016
• Last Update Submitted That Met QC Criteria: March 15, 2016
• Last Verified: June 1, 2000

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Heart Diseases; Cardiovascular Diseases; Hypertrophy; Cardiomyopathies; Cardiomyopathy, Hypertrophic
• Other Study ID Numbers: 1133; R01HL042467 (U.S. NIH Grant/Contract)