ESPE Abstracts

Differences of sex development (DSD) are congenital conditions with discordance between chromosomal, gonadal and/or anatomic sex. DSD can be syndromic or non-syndromic based on the presence or absence of somatic anomalies, respectively. Variants in several genes have been identified in association with errors of testis determination and male genital differentiation. However, despite technological advances, a genetic diagnosis is not achieved in nearly 50% of individuals presenting with 46,XY DSD. NR2F2 (nuclear receptor subfamily 2 group F member 2) encodes an orphan nuclear receptor, COUP-TFII (chicken ovalbumin upstream promoter transcription factor II). Variants in NR2F2 have been reported in XX individuals with the development of testicular tissue and abnormalities in the heart, the diaphragm and the eyelid.¹ This study describes a 2-year-old 46,XY boy presenting with micropenis, middle hypospadias and inguinal testes without associated somatic anomalies. Hormonal profile shows age-appropriate levels of luteinizing hormone (0.4 IU/L, normal <1.5), follicle-stimulating hormone (1.2 IU/L, normal <5), hCG-stimulated testosterone (705 ng/dL, normal 660 ± 410) and anti-Müllerian hormone (41 ng/mL, normal 13-167). Abdominopelvic ultrasonography was unremarkable with no Müllerian structures. Whole exome sequencing revealed a novel de novo heterozygous missense variant in NR2F2, NM_021005.4:c.737G>A resulting in p.Arg246His. The variant is absent in ancestry-matched populations and the gnomAD database (http://gnomad.broadinstitute.org/). It is located within a highly conserved region of the ligand-binding domain (LBD) and is predicted to be potentially damaging. The mutation, however, does not impact the nuclear localization or the stability of the protein. It has been shown that mutating specific residues in LBD can substantially reduce the COUP-TFII transcriptional activity.² Consistent with this, we observe that NR2F2^Arg246His showed a significant loss of inhibitory effect on the NR5A1-mediated activation of LH-β and INSL3 promoters, while maintaining the binding between the two proteins. Taken together, our results support the pathogenicity of the p.Arg246His variant in 46,XY DSD and expand the small but growing list of genes that are associated with both 46,XX and 46,XY DSD.

References: 1. Bashamboo A, et al. Am J Hum Genet. 2018;102:487-493. 2. Kruse SW, et al. Plos Bio. 2008;6:e227.