Hostname: page-component-78c5997874-dh8gc Total loading time: 0 Render date: 2024-11-17T17:23:34.288Z Has data issue: false hasContentIssue false
  • English
  • Français

Clinical and molecular characterisation of Holt–Oram syndrome focusing on cardiac manifestations

Published online by Cambridge University Press:  12 September 2014

Won Kyoung Jhang ,
Beom Hee Lee ,
Gu-Hwan Kim ,
Jin-Ok Lee  and
Han-Wook Yoo
Won Kyoung Jhang
Affiliation:
Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
Beom Hee Lee
Affiliation:
Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
Gu-Hwan Kim
Affiliation:
Medical Genetic Center, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
Jin-Ok Lee
Affiliation:
Medical Genetic Center, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
Han-Wook Yoo*
Affiliation:
Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea Medical Genetic Center, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
*
Correspondence to: H.-W. Yoo, Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Republic of Korea. Tel: 8 223 010 3374; Fax: 822 473 3725; E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Background: Holt–Oram syndrome is characterised by CHD and limb anomalies. Mutations in TBX5 gene, encoding the T-box transcription factor, are responsible for the development of Holt–Oram syndrome, but such mutations are variably detected in 30–75% of patients. Methods: Clinically diagnosed eight Holt–Oram syndrome patients from six families were evaluated the clinical characteristics, focusing on the cardiac manifestations, in particular, and molecular aetiologies. In addition to the investigation of the mutation of TBX5, SALL4, NKX2.5, and GATA4 genes, which are known to regulate cardiac development by physically and functionally interacting with TBX5, were also analyzed. Multiple ligation-dependent probe amplification analysis was performed to detect exonic deletion and duplication mutations in these genes. Results: All included patients showed cardiac septal defects and upper-limb anomalies. Of the eight patients, seven underwent cardiac surgery, and four suffered from conduction abnormalities such as severe sinus bradycardia and complete atrioventricular block. Although our patients showed typical clinical findings of Holt–Oram syndrome, only three distinct TBX5 mutations were detected in three families: one nonsense, one splicing, and one missense mutation. No new mutations were identified by testing SALL4, NKX2.5, and GATA4 genes. Conclusions: All Holt–Oram syndrome patients in this study showed cardiac septal anomalies. Half of them showed TBX5 gene mutations. To understand the genetic causes for inherited CHD such as Holt–Oram syndrome is helpful to take care of the patients and their families. Further efforts with large-scale genomic research are required to identify genes responsible for cardiac manifestations or genotype–phenotype relation in Holt–Oram syndrome.

Keywords

Holt–Oram syndromeCHD and skeletal malformationscardiac arrhythmiagenetic loci
Type
Original Articles
Information
Cardiology in the Young , Volume 25 , Supplement 6 , August 2015 , pp. 1093 - 1098
Copyright
© Cambridge University Press 2014 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Hoffman, JI, Kaplan, S. The incidence of congenital heart disease. J Am Coll Cardiol 2002; 39: 1890–1900.CrossRefGoogle ScholarPubMed
2. Wolf, M, Basson, CT. The molecular genetics of congenital heart disease: a review of recent developments. Curr Opin Cardiol 2010; 25: 192–197.CrossRefGoogle ScholarPubMed
3. Huang, JB, Liu, YL, Sun, PW, Lv, XD, Du, M, Fan, XM. Molecular mechanisms of congenital heart disease. Cardiovasc Pathol 2010; 19: e183–e193.Google ScholarPubMed
4. Pierpont, ME, Basson, CT, Benson, DW Jr, et al. 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 2007; 115: 3015–3038.CrossRefGoogle Scholar
5. Huang, T. Current advances in Holt-Oram syndrome. Curr Opin Pediatr 2002; 14: 691–695.CrossRefGoogle ScholarPubMed
6. Basson, CT, Huang, T, Lin, RC, et al. Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations. Proc Natl Acad Sci U S A 1999; 96: 2919–2924.CrossRefGoogle ScholarPubMed
7. Fan, C, Liu, M, Wang, Q. Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome. J Biol Chem 2003; 278: 8780–8785.CrossRefGoogle ScholarPubMed
8. Adamopoulos, S, Kokkinou, S, Parissis, JT, Kremastinos, DT. New insight into “heart-hand” syndromes: a newly discovered chromosomal abnormality in a family with “heart-hand” syndrome. Int J Cardiol 2004; 97: 129–132.Google Scholar
9. McDermott, DA, Bressan, MC, He, J, et al. TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome. Pediatr Res 2005; 58: 981–986.Google Scholar
10. Heinritz, W, Shou, L, Moschik, A, Froster, UG. The human TBX5 gene mutation database. Hum Mutat 2005; 26: 397.Google Scholar
11. Basson, CT, Solomon, SD, Weissman, B, et al. Genetic heterogeneity of heart-hand syndromes. Circulation 1995; 91: 1326–1329.Google Scholar
12. Basson, CT, Cowley, GS, Solomon, SD, et al. The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome). N Engl J Med 1994; 330: 885–891.Google Scholar
13. Newbury-Ecob, RA, Leanage, R, Raeburn, JA, Young, ID. Holt-Oram syndrome: a clinical genetic study. J Med Genet 1996; 33: 300–307.Google Scholar
14. Bossert, T, Walther, T, Gummert, J, Hubald, R, Kostelka, M, Mohr, FW. Cardiac malformations associated with the Holt-Oram syndrome – report on a family and review of the literature. Thorac Cardiovasc Surg 2002; 50: 312–314.CrossRefGoogle ScholarPubMed
15. Kohlhase, J, Chitayat, D, Kotzot, D, et al. SALL4 mutations in Okihiro syndrome (Duane-radial ray syndrome), acro-renal-ocular syndrome, and related disorders. Hum Mutat 2005; 26: 176–183.CrossRefGoogle ScholarPubMed
16. Akazawa, H, Komuro, I. Cardiac transcription factor Csx/Nkx2-5: its role in cardiac development and diseases. Pharmacol Ther 2005; 107: 252–268.Google Scholar
17. Misra, C, Sachan, N, McNally, CR, et al. Congenital heart disease-causing Gata4 mutation displays functional deficits in vivo. PLoS Genet 2012; 8: e1002690.CrossRefGoogle ScholarPubMed
18. Nadeau, M, Georges, RO, Laforest, B, et al. An endocardial pathway involving Tbx5, Gata4, and Nos3 required for atrial septum formation. Proc Natl Acad Sci U S A 2010; 107: 19356–19361.Google Scholar
19. Granados-Riveron, JT, Pope, M, Bu’lock, FA, et al. Combined mutation screening of NKX2-5, GATA4, and TBX5 in congenital heart disease: multiple heterozygosity and novel mutations. Congenit Heart Dis 2012; 7: 151–159.Google Scholar
20. Maitra, M, Schluterman, MK, Nichols, HA, et al. Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development. Dev Biol 2009; 326: 368–377.Google Scholar
21. Manning, N, Kaufman, L, Roberts, P. Genetics of cardiological disorders. Semin Fetal Neonatal Med 2005; 10: 259–269.CrossRefGoogle ScholarPubMed
22. Bruneau, BG, Logan, M, Davis, N, et al. Chamber-specific cardiac expression of Tbx5 and heart defects in Holt-Oram syndrome. Dev Biol 1999; 211: 100–108.Google Scholar
23. Holt, M, Oram, S. Familial heart disease with skeletal malformations. Br Heart J 1960; 22: 236–242.Google Scholar
24. Powell, CM, Michaelis, RC. Townes-Brocks syndrome. J Med Genet 1999; 36: 89–93.Google Scholar
25. Borozdin, W, Bravo Ferrer Acosta, AM, Bamshad, MJ, et al. Expanding the spectrum of TBX5 mutations in Holt-Oram syndrome: detection of two intragenic deletions by quantitative real time PCR, and report of eight novel point mutations. Hum Mutat 2006; 27: 975–976.Google Scholar
26. Heinritz, W, Moschik, A, Kujat, A, et al. Identification of new mutations in the TBX5 gene in patients with Holt-Oram syndrome. Heart 2005; 91: 383–384.Google Scholar
27. Lee, BH, Kim, YM, Kim, GH, Kim, YH, Yoo, HW. A familial case with Holt-Oram syndrome with a novel TBX5 mutation. J Genet Med 2012; 9: 98–100.CrossRefGoogle Scholar
28. Kohlhase, J, Schubert, L, Liebers, M, et al. Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy. J Med Genet 2003; 40: 473–478.CrossRefGoogle Scholar
29. Bruneau, BG. The developmental genetics of congenital heart disease. Nature 2008; 451: 943–948.CrossRefGoogle ScholarPubMed
30. Srivastava, D, Olson, EN. A genetic blueprint for cardiac development. Nature 2000; 407: 221–226.CrossRefGoogle ScholarPubMed
31. Postma, AV, van de Meerakker, JB, Mathijssen, IB, et al. A gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation. Circ Res 2008; 102: 1433–1442.Google Scholar
Supplementary material: File

Jhang supplementary material

Table S1

Download Jhang supplementary material(File)
File 15.1 KB