A case of 46,XY disorders of sex development with congenital heart disease caused by a GATA4 variant

Abstract

GATA4 is known to be a causative gene for congenital heart disease, but has also now been associated with disorders of sexual development (DSD). We here report a pathogenic variant of GATA4 in a 46,XY DSD patient with an atrial septal defect, identified by whole‐exome sequencing to be c.487C>T (p.Pro163Ser). This mutation resulted in reduced transcriptional activity of the downstream gene. When we compared this transcriptional activity level with other GATA4 variants, those that had been identified in patients with cardiac defects and DSD showed less activity than those in patients with cardiac defect only. This suggests that the normal development of the heart requires more strict regulation of GATA4 transcription than testicular development. Further, when the different variants were co‐expressed with wild‐type, the transcriptional activities were consistently lower than would be expected from an additive effect, suggesting a dominant‐negative impact of the variant via dimer formation of the GATA4 protein. Since these pathogenic GATA4 variants are occasionally identified in healthy parents, a threshold model of quantitative traits may explain the cardiac defect or DSD phenotypes that they cause.

Case Report: Longitudinal follow-up and testicular sperm extraction in a patient with a pathogenic NR5A1 (SF-1) frameshift variant: p.(Phe70Serfs*5)

“…Finally, the presence of tetralogy of Fallot is surprising and was not reported elsewhere in association with a mutated SF-1. However, we could not exclude an additional genetic anomaly in other genes associated with DSD and/or tetralogy of Fallot, GATA4 and ZFPM2/FOG2 genes, for example ( 48 , 49 ).…”

A Rare Case of Precocious Puberty in a Child with a Novel GATA-4 Gene Mutation: Implications for Disorders of Sex Development (DSD) and Review of the Literature

“…In the literature, 26 cases with 46,XY DSD due to the GATA4 gene have been reported until now ( Table 2 ) [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Only five cases were raised as female.…”

“…CHD was found in five patients, and three cases of them had atrial septal defects. Yui Shichiri et al suggested that GATA4 activity is mostly deficient in patients with both cardiac defects and DSD than that observed in patients with only CHD [ 18 ]. This conclusion was derived by analyzing the expressivity of the p.Pro163Ser variant of GATA4 in five different patients with CHD of which only one also presented a DSD.…”

“…This conclusion was derived by analyzing the expressivity of the p.Pro163Ser variant of GATA4 in five different patients with CHD of which only one also presented a DSD. In this way, they assumed that normal development of the heart required stricter regulation of GATA4 transcription than gonadal development [ 18 ].…”

“…Genetic conditions, such as syndromes or specific mutations, define the copresence of these disorders. GATA4 haploinsufficiency, a rare cause of 46,XY DSD, could cause a wide spectrum of genital abnormalities, including micropenis, cryptorchidism, and hypospadias, as reported in the 26 patients with DSD due to the GATA4 mutations that are included in previous studies [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ].…”