A GATA4 haploinsufficiency has been well described in patients with congenital heart defects (CHDs), whilst only a few studies have reported mutations related to a 46,XY disorder of sex development (DSD) phenotype. This study investigated the clinical phenotypes and molecular characteristics of two 46,XY DSD patients harboring GATA4 variants. Mutation analysis was performed using a targeted gene panel or whole-exome sequencing. The transactivation activity of each variant protein was examined by in vitro luciferase reporter assay using the AMH and SRY promoters. Subject 1 presented with a micropenis and hypospadias. Subject 2 showed complete female external genitalia with a 46,XY karyotype. Both patients were responsive to hCG stimulation tests and did not manifest CHD. A novel heterozygous variant, c.643A>G (p.R215G), in GATA4 was identified in Subject 1, whereas Subject 2 harbored a previously reported variant, c.1220C>A (p.P407Q), in GATA4 and a previously known pathogenic mutation, i.e., c.226C>T (p.Q76*) in the AR gene. The reporter assays using the SRY and AMH promoters revealed decreased transcriptional activity of both p.P407Q and p.R215G. However, the GATA4 p.P407Q variant was classified as likely benign. In conclusion, it is essential to integrate clinical features and endocrine findings when interpreting sequence variants.

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