Novel missense variants of ZFPM2/FOG2 identified in conotruncal heart defect patients do not impair interaction with GATA4.

Conotruncal heart defect (CTD) is a complex form of congenital heart disease and usually has a poor prognosis. ZFPM2/FOG2 encodes a transcription cofactor that interacts with GATA4 to regulate cardiac development. This regulation has been established in knockout mouse models that display a range of heart malformations, especially CTD. Although previous studies have identified several missense variants in ZFPM2/FOG2 that may cause CTD, it remains unclear whether they are involved in CTD pathogenesis because the study populations were limited and the functional status was unknown. 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. Four variants (p.V339I in one DORV, p.A426T in one DORV, p.M703L in three TOF, p.T843M in one TOF) were found in six patients, of which two are reported here for the first time. No copy number variations of the gene were detected. GST pull-down assays demonstrated that all potentially deleterious variants, including those previously reported, did not impair the interaction with GATA4, except for variant p.M544I and p.K737E, which subtly impaired the binding. Thus, these missense variants may be involved in other mechanisms underlying CTD or may be unrelated to CTD occurrence.