Cardiac homeobox gene NKX2-5 mutations and congenital heart disease: associations with atrial septal defect and hypoplastic left heart syndrome.
OBJECTIVE
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.
Elliott
David A
DA
Victor Chang Cardiac Research Institute, 384 Victoria Street, Darlinghurst 2010, Sydney, Australia.
Kirk
Edwin P
EP
Yeoh
Thomas
T
Chandar
Suchitra
S
McKenzie
Fiona
F
Taylor
Peter
P
Grossfeld
Paul
P
Fatkin
Diane
D
Jones
Owen
O
Hayes
Peter
P
Feneley
Michael
M
Harvey
Richard P
RP
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005192:Family Health; D005260:Female; D005801:Genes, Homeobox / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics; D006327:Heart Block / Q000235:genetics; D006329:Heart Conduction System / Q000473:pathology; D006330:Heart Defects, Congenital / Q000235:genetics*; D006344:Heart Septal Defects, Atrial / Q000235:genetics; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D017354:Point Mutation / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D012189:Retrospective Studies; D013223:Statistics as Topic; D014157:Transcription Factors; D014481:United States; D029867:Xenopus Proteins
D005819:Genetic Markers; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D014157:Transcription Factors; D029867:Xenopus Proteins