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

Published online by Cambridge University Press:  12 September 2014

Won Kyoung Jhang
Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
Beom Hee Lee
Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
Gu-Hwan Kim
Medical Genetic Center, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
Jin-Ok Lee
Medical Genetic Center, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
Han-Wook Yoo*
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:


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.

Original Articles
© Cambridge University Press 2014 

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