In this study, we identified a novel 2 bp insertion mutation, c.512InsGC p.170X, in NKX2.5 that causes ASDs, AVB, and ventricular noncompaction as well as syncope and sudden death. Multiple pieces of evidence indicate that c.512InsGC is a pathogenic mutation. First, c.512InsGC co-segregates with CHD in the family. Second, the mutation was not identified in 200 normal controls. Third, the c.512InsGC insertion is a frame-shift mutation and generates a truncated NKX2.5 protein that deletes the C-terminal 154 amino acids containing the second half of the HD domain and the entire NK2 domain. Forth, functional studies showed that contrary to wild type NKX2.5, the mutant NKX2.5 protein generated by c.512InsGC was distributed in both the cytoplasm and nuclei, and completely lost the transcription activation activity.
A novel finding from this study is that NKX2.5 mutation is associated with ventricular noncompaction. Ventricular noncompaction is sometimes referred to as “ventricular hypertrabeculation” and is a cardiomyopathy which may be caused by failed compaction of trabeculated muscle structures due to arrest of normal embryogenesis of the endocardium and myocardium [26
]. Our finding is consistent with results from knockout mice with ventricular-restricted deletion of NKX2.5
]. These NKX2.5
knockout mice exhibited massive trabecular muscle overgrowth. To the best of our knowledge, this is the first time that ventricular noncompaction was found in a human NKX2.5
mutation carrier. These results significantly expand the phenotypic spectrum of NKX2.5
mutations. The molecular mechanism by which a NKX2.5
mutation causes ventricular noncompaction is unknown. Ventricular noncompaction is a cardiac disorder associated with mutations in sarcomere genes [28
may regulate expression of some sarcomere genes, facilitating development of ventricular noncompaction.
mutation c.512InsGC is associated with syncope and sudden death. Two other mutations, Q170X identified in one ASD family and a double mutation Q170X/Q198X in another ASD family, were also previously reported to be associated with sudden death in families [29
The c.512InsGC insertion arose de novo
. This is the second de novo
mutation identified in NKX2.5
. The first de novo
mutation in NKX2.5
was a one bp C insertion at codon 167, and was identified in a single patient with ASDs and AVDs [23
We failed to identify any NKX2.5
mutation in 125 Chinese Han patients with CHD, suggesting that NKX2.5
mutations are rare in sporadic CHD cases. Our results are more consistent with several previously-reported studies [21
In conclusion, this study identified a novel, de novo mutation in NKX2.5 that is associated not only with ASDs, AVB, syncope, and sudden death, but also with ventricular noncompaction. The results provide insights into the molecular pathogenic mechanism of ventricular noncompaction.