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Clinical and molecular characterisation of Holt-Oram syndrome focusing on cardiac manifestations.
Cardiol Young. 2015 Aug; 25(6):1093-8.CY

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.

Authors+Show Affiliations

1Department of Pediatrics,Asan Medical Center Children's Hospital,University of Ulsan College of Medicine,Seoul,Korea.1Department of Pediatrics,Asan Medical Center Children's Hospital,University of Ulsan College of Medicine,Seoul,Korea.2Medical Genetic Center,Asan Medical Center Children's Hospital,University of Ulsan College of Medicine,Seoul,Korea.2Medical Genetic Center,Asan Medical Center Children's Hospital,University of Ulsan College of Medicine,Seoul,Korea.1Department of Pediatrics,Asan Medical Center Children's Hospital,University of Ulsan College of Medicine,Seoul,Korea.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25216260

Citation

Jhang, Won Kyoung, et al. "Clinical and Molecular Characterisation of Holt-Oram Syndrome Focusing On Cardiac Manifestations." Cardiology in the Young, vol. 25, no. 6, 2015, pp. 1093-8.
Jhang WK, Lee BH, Kim GH, et al. Clinical and molecular characterisation of Holt-Oram syndrome focusing on cardiac manifestations. Cardiol Young. 2015;25(6):1093-8.
Jhang, W. K., Lee, B. H., Kim, G. H., Lee, J. O., & Yoo, H. W. (2015). Clinical and molecular characterisation of Holt-Oram syndrome focusing on cardiac manifestations. Cardiology in the Young, 25(6), 1093-8. https://doi.org/10.1017/S1047951114001656
Jhang WK, et al. Clinical and Molecular Characterisation of Holt-Oram Syndrome Focusing On Cardiac Manifestations. Cardiol Young. 2015;25(6):1093-8. PubMed PMID: 25216260.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clinical and molecular characterisation of Holt-Oram syndrome focusing on cardiac manifestations. AU - Jhang,Won Kyoung, AU - Lee,Beom Hee, AU - Kim,Gu-Hwan, AU - Lee,Jin-Ok, AU - Yoo,Han-Wook, Y1 - 2014/09/12/ PY - 2014/9/13/entrez PY - 2014/9/13/pubmed PY - 2016/3/30/medline KW - CHD and skeletal malformations KW - Holt–Oram syndrome KW - cardiac arrhythmia KW - genetic loci SP - 1093 EP - 8 JF - Cardiology in the young JO - Cardiol Young VL - 25 IS - 6 N2 - 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. SN - 1467-1107 UR - https://www.unboundmedicine.com/medline/citation/25216260/Clinical_and_molecular_characterisation_of_Holt_Oram_syndrome_focusing_on_cardiac_manifestations_ L2 - https://www.cambridge.org/core/product/identifier/S1047951114001656/type/journal_article DB - PRIME DP - Unbound Medicine ER -