Mutations in human NKX2.5 cause a variety of cardiac anomalies and may account for a clinically significant portion of tetralogy of Fallot and idiopathic AV block. The coinheritance of NKX2.5 mutations with various congenital heart defects suggests that this transcription factor contributes to diverse cardiac developmental pathways.
Mutations in NKX2.5, a homeobox transcription factor, were reported to cause secundum atrial septal defects and result in atrioventricular (AV) conduction block during postnatal life. Associated phenotypes included AV block, which was the primary manifestation of cardiac disease, as well as atrial septal defect and ventricular septal defect. Ventricular septal defect was commonly associated with tetralogy of Fallot or double-outlet right ventricle. Ebstein’s anomaly and other tricuspid valve abnormalities were also present.
We recently described 3 heterozygote mutations in NKX2.5 that resulted in atrioventricular (AV) conduction block. Many genotype-positive individuals also had a secundum atrial septal defect (ASD). In kindreds with NKX2.5 mutation, there was a history of other congenital heart malformations in some family members including ventricular septal defect and tetralogy of Fallot (TOF). To further characterize the role of NKX2.5 in human cardiac morphogenesis, we have identified additional mutations and defined the clinical phenotypes produced by these mutations.
In this report, 7 additional NKX2.5 mutations are described. As reported previously, AV conduction abnormalities and ASD occurred commonly. However, we also found evidence of several different types of ventricular septal defects (VSD) that were sometimes associated with double-outlet right ventricle and tetralogy of Fallot. In addition, tricuspid valve abnormalities, including Ebstein’s anomaly, were noted in some individuals. These observations illustrate an essential role for NKX2.5 in atrial, ventricular, and conotruncal septation, AV valve formation, and maintenance of AV conduction.
Observations in this study provide additional evidence for a role of NKX2.5 beyond early cardiac progenitor commitment; the coinheritance of heterozygous NKX2.5 mutations with various congenital heart defects suggests that this transcription factor contributes to diverse cardiac developmental pathways including atrial, ventricular, and conotruncal septation, AV conduction, and AV valve formation. As described previously, AV block and ASD are common in kindreds in whom congenital heart disease is due to NKX2.5 mutation. Additionally, NKX2.5 mutation causes AV block without associated congenital heart defects, and, as demonstrated in the patients we studied, AV block was the principal clinical finding in 23% of genotype-positive individuals. Further, based on results of the present study, NKX2.5 mutation may account for a clinically significant portion of idiopathic AV block.
However, cardiovascular defects resulting from NKX2.5 mutations extend beyond AV block and ASD. For example, VSD was present in 31% of genotype-positive individuals, including conoventricular VSD associated with tetralogy of Fallot and double-outlet, right ventricle and muscular VSD that closed spontaneously in infancy. Results of this study suggest that in individuals without a del22q11, NKX2.5 mutations may account for a significant portion of conotruncal defects. Abnormalities of the tricuspid valve were also present (15%), and for the first time, we have identified a genetic cause of Ebstein’s anomaly. Based on the diversity of cardiac phenotypes, we hypothesize that many additional forms of congenital heart disease may result from NKX2.5 mutations. The small sample size we studied does not allow estimation of a portion of cardiac anomalies resulting from NKX2.5; our study is further limited by concentration on mutations in coding sequences only.
Based on results of the present studies, NKX2.5 appears to be a likely candidate gene for a number of forms of cardiovascular disease in the young.
Source: Excerpt of Study, The Journal of Clinical Investigation, Vol 104, 1999