CLINICAL RESEARCH: CONGENITAL HEART DISEASE
Cardiac homeobox gene NKX2-5 mutations and congenital heart disease
Associations with atrial septal defect and hypoplastic left heart syndrome
David A. Elliott, PhD*,
Edwin P. Kirk, MBBS*  ,
Thomas Yeoh, MBBS*,
Suchitra Chandar, MBBS*,
Fiona McKenzie, MBBS ,
Peter Taylor, BAppSc,
Paul Grossfeld, MD||,
Diane Fatkin, MD*,
Owen Jones, MBBS,
Peter Hayes, MBBS*,
Michael Feneley, MD* and
Richard P. Harvey, PhD*,*
* Victor Chang Cardiac Research Institute, Sydney, Australia
Sydney Children’s Hospital, Sydney, Australia
University of New South Wales, Sydney, Australia
Hunter Genetics, Newcastle, Australia
|| University of California at San Diego/Children’s Hospital, San Diego, California, USA
Manuscript received January 15, 2003;
revised manuscript received January 21, 2003,
accepted February 20, 2003.
* Reprint requests and correspondence: Dr. Richard P. Harvey, Victor Chang Cardiac Research Institute, 384 Victoria Street, Darlinghurst 2010, Australia.
r.harvey{at}victorchang.unsw.edu.au
OBJECTIVES: We sought to examine the importance of mutations in the cardiac transcription factor gene NKX2-5 in patients with an atrial septal defect (ASD), patent foramen ovale (PFO), or hypoplastic left heart syndrome (HLHS).
BACKGROUND: Mutations in NKX2-5 have been found in families showing secundum ASD and atrioventricular (AV) conduction block and in some individuals with tetralogy of Fallot. The prevalence of NKX2-5 mutations in sporadic cases of ASD/PFO and other forms of congenital heart disease is unknown.
METHODS: A cohort of 146 individuals with secundum ASD, PFO complicated by paradoxical embolism, or HLHS were evaluated. Patients with ASD or PFO were ascertained irrespective of family history or associated cardiac abnormalities. The coding region of the NKX2-5 locus was amplified by polymerase chain reaction and sequenced.
RESULTS: Among 102 ASD and 25 PFO patients screened, 13 patients (10%) had a positive family history and 5 patients (4%) had AV conduction block. We found one previously documented NKX2-5 missense mutation, T178M, in members of a family with ASD without AV conduction block. One NKX2-5 mutation-positive child from this family had HLHS, although no mutations were subsequently found in 18 patients with sporadic or familial HLHS. In a second ASD family without AV conduction block, we found a missense change, E21Q, previously reported as pathogenic. Because this change did not segregate with disease status, we propose that it is a non-disease–causing polymorphism.
CONCLUSIONS: Our findings suggest that NKX2-5 mutations are a relatively infrequent cause of sporadic ASD and HLHS. Screening for NKX2-5 mutations may be warranted in individuals with ASD and a positive family history, irrespective of the presence or absence of AV conduction block.
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Abbreviations and Acronyms
| | ASD | | atrial septal defect | | AV | | atrioventricular | | CHD | | congenital heart disease | | DNA | | deoxyribonucleic acid | | HLHS | | hypoplastic left heart syndrome | | PCR | | polymerase chain reaction | | PFO | | patent foramen ovale | | TOF | | tetralogy of Fallot |
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