FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 330:885-891 March 31, 1994 Number 13 Next

	Full Text Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited Related Article PubMed Citation

ABSTRACT

Background The Holt-Oram syndrome is an autosomal dominant condition characterized by skeletal abnormalities that are frequently accompanied by congenital cardiac defects. The cause of these disparate clinical features is unknown. To identify the chromosomal location of the Holt-Oram syndrome gene, we performed clinical and genetic studies.

Methods Two large families with the Holt-Oram syndrome were evaluated by radiography of the hands, electrocardiography, and transthoracic echocardiography. Genetic-linkage analyses were performed with polymorphic DNA loci dispersed throughout the genome to identify a locus that was inherited with the Holt-Oram syndrome in family members.

Results A total of 19 members of Family A had Holt-Oram syndrome with mild-to-moderate skeletal deformities, including triphalangeal thumbs and carpal-bone dysmorphism. All affected members of Family A had moderate-to-severe congenital cardiac abnormalities, such as ventricular or atrial septal defects or atrioventricular-canal defects. Eighteen members of a second kindred (Family B) had Holt-Oram syndrome with moderate-to-severe skeletal deformities, including phocomelia. Twelve of the affected members had no cardiac defects; six had only atrial septal defects. Genetic analyses demonstrated linkage of the disease in each family to polymorphic loci on the long arm of chromosome 12 (combined multipoint lod score, 16.8). These data suggest odds greater than 10¹⁶:1 that the genetic defect for Holt-Oram syndrome is present on the long arm of chromosome 12 (12q2).

Conclusions Mutations in a gene on chromosome 12q2 can produce a wide range of disease phenotypes characteristic of the Holt-Oram syndrome. This gene has an important role in both skeletal and cardiac development.

Source Information

From the Cardiovascular Division, Department of Medicine (C.T.B., S.D.S., C.E.S.), and the Department of Radiology (B.W.), Brigham and Women's Hospital, Boston; Harvard Medical School, Boston (C.T.B., S.D.S., C.E.S.); the Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston (G.S.C., J.G.S.); the Department of Radiology, Children's Memorial Hospital, Chicago (A.K.P.); and the Cardiovascular Division, Department of Medicine, Johns Hopkins Hospital, Baltimore (T.A.T.).

Address reprint requests to Dr. Christine Seidman at the Department of Genetics, Harvard Medical School, Alpert Bldg., Rm. 533, 200 Longwood Ave., Boston, MA 02115.

Full Text of this Article

This article has been cited by other articles:

• Meder, B., Katus, H. A., Rottbauer, W. (2008). Right into the heart of microRNA-133a. Genes Dev. 22: 3227-3231 [Abstract] [Full Text]  
• McDermott, D. A., Hatcher, C. J., Basson, C. T. (2008). Atrial Fibrillation and Other Clinical Manifestations of Altered TBX5 Dosage in Typical Holt-Oram Syndrome. Circ. Res. 103: e96-e96 [Full Text]  
• Postma, A. V., van de Meerakker, J. B.A., Mathijssen, I. B., Barnett, P., Christoffels, V. M., Ilgun, A., Lam, J., Wilde, A. A.M., Lekanne Deprez, R. H., Moorman, A. F.M. (2008). A Gain-of-Function TBX5 Mutation Is Associated With Atypical Holt-Oram Syndrome and Paroxysmal Atrial Fibrillation. Circ. Res. 102: 1433-1442 [Abstract] [Full Text]  
• (2007). Picture of the Month--Diagnosis. Arch Pediatr Adolesc Med 161: 712-712 [Full Text]  
• Pierpont, M. E., Basson, C. T., Benson, D. W. Jr, Gelb, B. D., Giglia, T. M., Goldmuntz, E., McGee, G., Sable, C. A., Srivastava, D., Webb, C. L. (2007). Genetic Basis for Congenital Heart Defects: Current Knowledge: A Scientific Statement From the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: Endorsed by the American Academy of Pediatrics. Circulation 115: 3015-3038 [Abstract] [Full Text]  
• Varma, P. K, Padmakumar, R., Harikrishnan, S., Koshy, T., Neelakandhan, K. S (2006). Holt-Oram Syndrome with Hemiazygous Continuation of Inferior Vena Cava. Asian Cardiovasc. Thorac. Ann. 14: 161-163 [Abstract] [Full Text]  
• Pizard, A., Burgon, P. G., Paul, D. L., Bruneau, B. G., Seidman, C. E., Seidman, J. G. (2005). Connexin 40, a Target of Transcription Factor Tbx5, Patterns Wrist, Digits, and Sternum. Mol. Cell. Biol. 25: 5073-5083 [Abstract] [Full Text]  
• James, M. A., Green, H. D., McCarroll, H. R. Jr., Manske, P. R. (2004). The Association of Radial Deficiency with Thumb Hypoplasia. JBJS 86: 2196-2205 [Abstract] [Full Text]  
• Moskowitz, I. P. G., Pizard, A., Patel, V. V., Bruneau, B. G., Kim, J. B., Kupershmidt, S., Roden, D., Berul, C. I., Seidman, C. E., Seidman, J. G. (2004). The T-Box transcription factor Tbx5 is required for the patterning and maturation of the murine cardiac conduction system. Development 131: 4107-4116 [Abstract] [Full Text]  
• Sepulveda, W., Enriquez, G., Martinez, J. L., Mejia, R. (2004). Holt-Oram Syndrome: Contribution of Prenatal 3-Dimensional Sonography in an Index Case. J Ultrasound Med 23: 983-987 [Full Text]  
• Rallis, C., Bruneau, B. G., Del Buono, J., Seidman, C. E., Seidman, J. G., Nissim, S., Tabin, C. J., Logan, M. P. O. (2003). Tbx5 is required for forelimb bud formation and continued outgrowth. Development 130: 2741-2751 [Abstract] [Full Text]  
• Fan, C, Duhagon, M A, Oberti, C, Chen, S, Hiroi, Y, Komuro, I, Duhagon, P I, Canessa, R, Wang, Q (2003). Novel TBX5 mutations and molecular mechanism for Holt-Oram syndrome. J. Med. Genet. 40: e29-29 [Full Text]  
• Agarwal, P., Wylie, J. N., Galceran, J., Arkhitko, O., Li, C., Deng, C., Grosschedl, R., Bruneau, B. G. (2003). Tbx5 is essential for forelimb bud initiation following patterning of the limb field in the mouse embryo. Development 130: 623-633 [Abstract] [Full Text]  
• Sakata, Y., Kamei, C. N., Nakagami, H., Bronson, R., Liao, J. K., Chin, M. T. (2002). Ventricular septal defect and cardiomyopathy in mice lacking the transcription factor CHF1/Hey2. Proc. Natl. Acad. Sci. USA 99: 16197-16202 [Abstract] [Full Text]  
• Feng, Q., Song, W., Lu, X., Hamilton, J. A., Lei, M., Peng, T., Yee, S.-P. (2002). Development of Heart Failure and Congenital Septal Defects in Mice Lacking Endothelial Nitric Oxide Synthase. Circulation 106: 873-879 [Abstract] [Full Text]  
• Garrity, D. M., Childs, S., Fishman, M. C. (2002). The heartstrings mutation in zebrafish causes heart/fin Tbx5 deficiency syndrome. Development 129: 4635-4645 [Abstract] [Full Text]  
• HUANG, T., LOCK, J.E, MARSHALL, A.C, BASSON, C., SEIDMAN, J.G., SEIDMAN, C.E. (2002). Causes of Clinical Diversity in Human TBX5 Mutations. Cold Spring Harb Symp Quant Biol 67: 115-120 [Abstract]  
• Ghosh, T. K., Packham, E. A., Bonser, A. J., Robinson, T. E., Cross, S. J., Brook, J. D. (2001). Characterization of the TBX5 binding site and analysis of mutations that cause Holt-Oram syndrome. Hum Mol Genet 10: 1983-1994 [Abstract] [Full Text]  
• Ferrari, V. A., Scott, C. H., Holland, G. A., Axel, L., St. John Sutton, M. (2001). Ultrafast three-dimensional contrast-enhanced magnetic resonance angiography and imaging in the diagnosis of partial anomalous pulmonary venous drainage. J Am Coll Cardiol 37: 1120-1128 [Abstract] [Full Text]  
• Lee, T. C., Zhao, Y. D., Courtman, D. W., Stewart, D. J. (2000). Abnormal Aortic Valve Development in Mice Lacking Endothelial Nitric Oxide Synthase. Circulation 101: 2345-2348 [Abstract] [Full Text]  
• Brickner, M. E., Hillis, L. D., Lange, R. A. (2000). Congenital Heart Disease in Adults- First of Two Parts. NEJM 342: 256-263 [Full Text]  
• Satoda, M., Pierpont, M. E. M., Diaz, G. A., Bornemeier, R. A., Gelb, B. D. (1999). Char Syndrome, an Inherited Disorder With Patent Ductus Arteriosus, Maps to Chromosome 6p12-p21. Circulation 99: 3036-3042 [Abstract] [Full Text]  
• Basson, C. T., Huang, T., Lin, R. C., Bachinsky, D. R., Weremowicz, S., Vaglio, A., Bruzzone, R., Quadrelli, R., Lerone, M., Romeo, G., Silengo, M., Pereira, A., Krieger, J., Mesquita, S. F., Kamisago, M., Morton, C. C., Pierpont, M. E. M., Muller, C. W., Seidman, J. G., Seidman, C. E. (1999). Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations. Proc. Natl. Acad. Sci. USA 96: 2919-2924 [Abstract] [Full Text]  
• Horb, M., Thomsen, G. (1999). Tbx5 is essential for heart development. Development 126: 1739-1751 [Abstract]  
• Bohm, M. (1998). Holt-Oram Syndrome. Circulation 98: 2636-2637 [Full Text]  
• Benson, D. W., Sharkey, A., Fatkin, D., Lang, P., Basson, C. T., McDonough, B., Strauss, A. W., Seidman, J. G., Seidman, C. E. (1998). Reduced Penetrance, Variable Expressivity, and Genetic Heterogeneity of Familial Atrial Septal Defects. Circulation 97: 2043-2048 [Abstract] [Full Text]  
• Grover, J., Chen, X.-N., Korenberg, J. R., Roughley, P. J. (1995). The Human Lumican Gene. J. Biol. Chem. 270: 21942-21949 [Abstract] [Full Text]  
• Britz-Cunningham, S. H., Shah, M. M., Zuppan, C. W., Fletcher, W. H. (1995). Mutations of the Connexin43 Gap-Junction Gene in Patients with Heart Malformations and Defects of Laterality. NEJM 332: 1323-1330 [Abstract] [Full Text]  
• Basson, C. T., Solomon, S. D., Weissman, B., MacRae, C. A., Poznanski, A. K., Prieto, F., de la Fuente, S. R., Pease, W. E., Levin, S.E., Holmes, L. B., Seidman, J.G., Seidman, C. E. (1995). Genetic Heterogeneity of Heart-Hand Syndromes. Circulation 91: 1326-1329 [Abstract] [Full Text]  
• Payne, R. M., Johnson, M. C., Grant, J. W., Strauss, A. W. (1995). Toward a Molecular Understanding of Congenital Heart Disease. Circulation 91: 494-504 [Abstract] [Full Text]  
• Dietz, H. C., Pyeritz, R. E. (1994). Molecular Biology -- To the Heart of the Matter. NEJM 330: 930-932 [Full Text]