Five DNA sequence variants affecting variably conserved residues of ZFPM2/FOG2 were identified in patients with TOF type or ventricular septal defect type of DORV.
The six pathogenic variations were identified on the genes CHD7 (CHARGE syndrome), CITED2 (tetralogy of Fallot, ventricular septal defect and atrial septal defect), ZFPM2 (tetralogy of Fallot), MYH6 (atrial septal defect, familial isolated dilated cardiomyopathy) and, in two cases, KMT2D (Kabuki syndrome).
In P2, we identified a novel nonsynonymous SNV in ZFPM2 (NM_012082.3:c.1576C>T), a known causative gene for TOF, which may act as a protective variant downstream of TBX1, haploinsufficiency of which is responsible for congenital heart disease in individuals with 22q11DS.
In this report, we screened a larger CTD population, which comprised 145 tetralogy of Fallot (TOF), 37 double-outlet ventricle outflow (DORV), and 18 transposition of the great artery (TGA), to investigate exon mutations as well as copy number variations in ZFPM2/FOG2.
In human, while FOG-2 mutations have been identified in sporadic cases of tetralogy of Fallot, no mutations are described to be associated with impaired gonadal function.
Aberrant methylation status at the promoter CpG island shore of ZFPM2 gene may be associated with its gene transcription regulation in the TOF patients.
In the present review, we hypothesize that mutations in the GATA binding protein 4 (GATA-4)/friend of GATA-2 transcriptional complex and NKX2.5 gene may play a role in the abnormal migration and behavior of precardiac cells during heart development in patients with ToF.
Aberrant methylation statuses of the NKX2-5 gene body and HAND1 promoter regions are associated with the regulation of gene transcription in TOF patients and may play an important role in the pathogenesis of TOF.
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.
Numerous mutations in NKX2-5 gene have been reported in CHD patients, including atrial septal defect, ventricular septal defect (VSD) and tetrology of Fallot.
Evaluation of candidate loci in a large kindred segregating autosomal dominant ToF with reduced penetrance culminated in identification of a missense mutation (G274D) in JAG1, the gene encoding jagged1, a Notch ligand expressed in the developing right heart.
JAG1 mutations have been associated with several disorders including the multi-system dominant disorder Alagille syndrome, and some cases of tetralogy of Fallot (although these may represent variable expressivity of Alagille syndrome).
A specific G274D mutation in the second epidermal growth factor repeat of the Jagged-1 was found to correlate with tetralogy of Fallot symptoms but not with usual Alagille syndrome phenotypes.