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

• Published in: Cardiology in the young Vol. 25; no. 6; pp. 1093 - 1098
• Main Authors: Jhang, Won Kyoung, Lee, Beom Hee, Kim, Gu-Hwan, Lee, Jin-Ok, Yoo, Han-Wook
• Format: Journal Article
• Language: English
• Published: Cambridge, UK Cambridge University Press 01.08.2015
• Subjects: Abnormalities, Multiple - genetics; Abnormalities, Multiple - surgery; Child; Child, Preschool; Female; GATA4 Transcription Factor - genetics; Heart Defects, Congenital - genetics; Heart Defects, Congenital - surgery; Heart Septal Defects, Atrial - genetics; Heart Septal Defects, Atrial - surgery; Homeobox Protein Nkx-2.5; Homeodomain Proteins - genetics; Humans; Infant; Infant, Newborn; Lower Extremity Deformities, Congenital - genetics; Lower Extremity Deformities, Congenital - surgery; Male; Mutation; Original Articles; Pedigree; T-Box Domain Proteins - classification; T-Box Domain Proteins - genetics; Transcription Factors - genetics; Upper Extremity Deformities, Congenital - genetics; Upper Extremity Deformities, Congenital - surgery; CHD and skeletal malformations; cardiac arrhythmia; Holt–Oram syndrome; genetic loci
• ISSN: 1047-9511; 1467-1107
• DOI: 10.1017/S1047951114001656

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.