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Two novel frameshift mutations in NKX2.5 result in novel features including visceral inversus and sinus venosus type ASD
  1. Y Watanabe1,2,
  2. D W Benson3,
  3. S Yano2,4,
  4. T Akagi2,
  5. M Yoshino2,
  6. J C Murray1
  1. 1Department of Pediatrics, University of Iowa, Iowa City, IA, USA
  2. 2Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan
  3. 3Children’s Hospital Medical Center of Cincinnati, Cardiology Department, Location C, 4th Floor, 3333 Burnet Avenue, Cincinnati, OH, USA
  4. 4Medical Genetics, Department of Pediatrics, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA
  1. Correspondence to:
 Dr J C Murray, Department of Pediatrics, The University of Iowa, 140 EMRB Iowa City, IA 52242, USA;

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Recently, heterozygous mutations of human NKX2.5 were identified in patients with congenital heart disease.1,2 The most common phenotypes were progressive atrioventricular conduction delays (AV block) and secundum atrial septal defect (ASD), but other anatomical abnormalities, such as ventricular septal defect, tetralogy of Fallot, or tricuspid valve abnormalities, including Ebstein’s anomaly, and progressive left ventricular failure, were also reported. These findings strongly suggest that NKX2.5 is important in the later stages of heart development and maturation in addition to its role in cardiac progenitor commitment and patterning in the developing heart.

To characterise further the genotype-phenotype correlation of NKX2.5 mutations, we used NKX2.5 as a candidate gene in two kindreds where subjects in multiple generations had congenital heart disease and AV block. In this report, we describe phenotypes in two families with novel frameshift mutations in NKX2.5. The findings suggest an expanded population of subjects who could now be examined for mutations within this transcription factor and its upstream and downstream regulatory elements.



All studies were carried out in accordance with the institutional guidelines for human research. Subjects were evaluated by history, review of medical records, physical examination, 12 lead electrocardiogram (ECG), and two dimensional transthoracic echocardiography with colour flow Doppler. Cardiac catheterisation, abdominal echography, and/or cardiac surgery have been performed in some subjects.

Following the methods of Benson et al,1 the products, including all coding regions and intervening intron of NKX2.5, were amplified with the primers (1F and 4R) in a single polymerase chain reaction (PCR), using standard conditions and concentrations of reagents. Products were analysed on standard 1% agarose gels and stained with ethidium bromide. Sequencing primers used were previously designed for specific region sequencing1 and carried out on the Applied Biosystems DNA Sequencing system (Model 373 or 377). For family 1, …

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