title: Clinical and molecular characterisation of Holt-Oram syndrome focusing on cardiac manifestations.
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.affiliation: 1Department of Pediatrics,Asan Medical Center Children's Hospital,University of Ulsan College of Medicine,Seoul,Korea.
authors.forename: Won Kyoung
authors.initials: WK
authors.lastname: Jhang
authors.affiliation: 1Department of Pediatrics,Asan Medical Center Children's Hospital,University of Ulsan College of Medicine,Seoul,Korea.
authors.forename: Beom Hee
authors.initials: BH
authors.lastname: Lee
authors.affiliation: 2Medical Genetic Center,Asan Medical Center Children's Hospital,University of Ulsan College of Medicine,Seoul,Korea.
authors.forename: Gu-Hwan
authors.initials: GH
authors.lastname: Kim
authors.affiliation: 2Medical Genetic Center,Asan Medical Center Children's Hospital,University of Ulsan College of Medicine,Seoul,Korea.
authors.forename: Jin-Ok
authors.initials: JO
authors.lastname: Lee
authors.affiliation: 1Department of Pediatrics,Asan Medical Center Children's Hospital,University of Ulsan College of Medicine,Seoul,Korea.
authors.forename: Han-Wook
authors.initials: HW
authors.lastname: Yoo
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000601:surgery; D006344:Heart Septal Defects, Atrial / Q000235:genetics* / Q000601:surgery; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D038061:Lower Extremity Deformities, Congenital / Q000235:genetics* / Q000601:surgery; D008297:Male; D009154:Mutation; D010375:Pedigree; D020825:T-Box Domain Proteins / Q000145:classification* / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D038062:Upper Extremity Deformities, Congenital / Q000235:genetics* / Q000601:surgery
chemical_list: D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; C472575:SALL4 protein, human; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D014157:Transcription Factors
keywords: CHD and skeletal malformations; Holt–Oram syndrome; cardiac arrhythmia; genetic loci