GATA4 gene variants in 46,XY differences of sex development: report of four cases and literature review

Abstract Objectives 46,XY differences of sex development (DSD) comprise a heterogeneous group of congenital conditions affecting chromosomal, gonadal or anatomical sex differentiation. GATA4 is essential for cardiac and gonadal development, although its role in DSD is not fully understood. We report four 46,XY DSD cases with GATA4 variants from our center and performed a literature review. Case presentation Case 1 presented with ambiguous genitalia, persistent Müllerian structures, and complex congenital heart disease; a GATA4 variant (p.Cys239Arg) was identified, and gonadectomy revealed atrophic testes. Case 2 had penoscrotal hypospadias and a ventricular septal defect, carrying a synonymous GATA4 variant (p.Cys275=) and showing normal hormonal evaluation and pubertal development. Case 3 presented with perineal hypospadias and a GATA4 variant (p.Val305Ile), along with a maternally inherited RET mutation; his twin brother, carrying the same variants, had no DSD. Both exhibited spontaneous puberty. Case 4 presented with isolated hypospadias and a GATA4 variant (p.Arg261GLn) without cardiac anomalies. Conclusions GATA4 should be included in genetic panels for 46,XY DSD. Our work expand the clinical and molecular spectrum of GATA 4 -associated 46,XY DSD and our review support the relevance of zinc finger domain variants in gonadal development. Phenotypic variability among carriers supports variable expressivity and incomplete penetrance.