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.
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).