已知GATA4是先天性心脏病的致病基因,但现在也与性发育障碍（DSD）有关。我们在这里报道了46，XYDSD患者中GATA4的致病变体，通过全外显子组测序鉴定为c.487C>T（p。Pro163Ser）。该突变导致下游基因的转录活性降低。当我们将这种转录活性水平与其他GATA4变体进行比较时，在心脏缺陷和DSD患者中发现的患者的活动比仅心脏缺陷患者的活动少.这表明心脏的正常发育需要比睾丸发育更严格的GATA4转录调节。Further,当不同的变体与野生型共表达时，转录活性始终低于加性效应的预期，提示通过GATA4蛋白的二聚体形成对变体的显性负面影响。由于这些致病性GATA4变体偶尔在健康父母中被发现，数量性状的阈值模型可以解释它们引起的心脏缺陷或DSD表型.
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.
