Analysis of variants in GATA4 and FOG2/ZFPM2 demonstrates benign contribution to 46,XY disorders of sex development

Jocelyn A. van den Bergen, Gorjana Robevska, Stefanie Eggers, Stefan Riedl, Sonia R. Grover, Philip B. Bergman, Chris Kimber, Ashish Jiwane, Sophy Khan, Csilla Krausz, Jamal Raza, Irum Atta, Susan R. Davis, Makato Ono, Vincent Harley, Sultana M.H. Faradz, Andrew H. Sinclair, Katie L. Ayers

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Background: GATA-binding protein 4 (GATA4) and Friend of GATA 2 protein (FOG2, also known as ZFPM2) form a heterodimer complex that has been shown to influence transcription of genes in a number of developmental systems. Recent evidence has also shown these genes play a role in gonadal sexual differentiation in humans. Previously we identified four variants in GATA4 and an unexpectedly large number of variants in ZFPM2 in a cohort of individuals with 46,XY Differences/Disorders of Sex Development (DSD) (Eggers et al, Genome Biology, 2016; 17: 243). Method: Here, we review variant curation and test the functional activity of GATA4 and ZFPM2 variants. We assess variant transcriptional activity on gonadal specific promoters (Sox9 and AMH) and variant protein–protein interactions. Results: Our findings support that the majority of GATA4 and ZFPM2 variants we identified are benign in their contribution to 46,XY DSD. Indeed, only one variant, in the conserved N-terminal zinc finger of GATA4, was considered pathogenic, with functional analysis confirming differences in its ability to regulate Sox9 and AMH and in protein interaction with ZFPM2. Conclusions: Our study helps define the genetic factors contributing to 46,XY DSD and suggests that the majority of variants we identified in GATA4 and ZFPM2/FOG2 are not causative.

Original languageEnglish
Article numbere1095
Number of pages14
JournalMolecular Genetics and Genomic Medicine
Issue number3
Publication statusPublished - Mar 2020


  • disorders of sexual development
  • FOG2
  • functional analysis
  • GATA4
  • mutations
  • ZFPM2

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