Identification and functional analysis of fourteen NR5A1 variants in patients with the 46 XY disorders of sex development.

Human sex determination and differentiation is a complex process, during which NR5A1 plays a central role via the transcriptional regulation of key modulators involved in steroidogenesis. Approximately 8-15% of 46,XY DSD are caused by variants in the NR5A1 gene. Therefore, screening for variants in the NR5A1 gene was performed in a Chinese cohort of sixty-two 46,XY DSD patients with no AR or SRD5A2 variants via next-generation sequencing (NGS). Fourteen variants in the NR5A1 gene were identified in 16 patients from 14 unrelated families, including nine novel variants. These variants included eight heterozygote missense variants, two heterozygote frameshift variants, two heterozygote nonsense variants, one heterozygote nonframeshift deletion-insertion variant, and one homozygous missense variant. Functional assays showed that the transcriptional activity of the 11 variants was significantly reduced. In this study, 11 NR5A1 pathogenic variants were identified. These novel variants further expand the existing spectrum of the NR5A1 variants associated with 46,XY DSD, which will, in turn, assist in the molecular diagnosis of DSD.

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