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Increased Expression ofZFPM2BypassesSRYto Drive 46,XX Testicular Development: A New Mechanism of 46,XX DSD
Leah Ragno, na1, Daphne Yang, BA1, Trisha R. Bhatti, MD2, Jonathan P. Bradfield, MS3, Diana K. Bowen, MD4, Katheryn L. Grand, GC2, Hakon Hakonarson, MD, PhD2, Thomas F. Kolon, MD2, Joseph Glessner, PhD2, M. Celeste Simon, PhD1, Nicolas Skuli, PhD1, Maria G. Vogiatzi, MD2, Marie A. Guerraty, MD, PhD1, Matthew A. Deardorff, MD, PhD2, Louise C. Pyle, MD, PhD4.
1University of Pennsylvania, Philadelphia, PA, USA, 2Children's Hospital of Philadelphia, Philadelphia, PA, USA, 3Quantinuum Research LLC, Philadelphia, PA, USA, 4Children's National Hospital, Washington, DC, USA.

BACKGROUND: We present a patient with a novel cause of 46,XX Intersex/Differences of Sex Development (IDSD). Genome-wide array from blood showed 46,XX with a chromosome 8q duplication, containing 257 OMIM genes including ZFPM2 and CYP11B1. Congenital adrenal hyperplasia testing was negative, testosterone was elevated, and SRY was absent. The infant had a uterus, one streak ovary (<5% 8q duplication) and one testicle (75% 8q duplication). We hypothesized that mosaic ZFPM2 duplication resulted in localized ZFPM2 over-expression and testicular development. In typical testicular development, ZFPM2 and its binding partner, GATA4, drive expression of the SRY master regulator.
METHODS: We completed genome-wide arrays on patient blood and gonadal tissues, in addition to single-cell fibroblast clones from skin. We evaluated expression networks in the gonads using RNAseq.
RESULTS: RNAseq from gonadal tissue containing the duplication showed increased dosage of ZFPM2, and upregulation the early testis development network. SOX9 (FC=39.2, p=1.1x10-121) and NR5A1 (FC=1.4, p=4.8x10-4) interact to produce the functional marker of fetal Sertoli cells AMH (FC=108.4, p=2.3x10-56) and inhibit female sexual differentiation. Several components of the testicular sex development pathway were upregulated in addition to SOX9 and AMH, including the pro-testicular transcription factor MAP3K1 (FC=1.5, p=5.4x10-6), DMRT1 (FC=13.9, p=1.5x10-13), LHX9 (FC=2.5, p=2.2x10-15), DHH (FC=12.0, p=2.5x10-32), PTGDS (FC=2.5, p=8.6x10-20), and SOX8 (FC=10.9, p=6.2x10-11). ZFPM2 may function as a master temporal and spatial regulator of mammalian testicular organogenesis whose increased dosage elicits significant and cascading downstream effects. PTGDS (prostaglandin D2 synthase). Further, components of the ovarian WNT-signaling pathway were repressed, including LEF1 (FC=-3.7, p=2.1x10-23) and FOXL2 (FC=-8.1, p=1.2x10-41).
CONCLUSIONS: We have shown that increased ZPFM2 dosage can induce 46,XX testicular development in a manner not dependent on SRY. This contravenes the previous understanding that GATA4/ZFPM2 drives testicular development through SRY. ZFPM2 may modulate numerous critical sex development genes including transcription factors otherwise thought to be downstream of SRY (MAP3K1, SOX9, AMH). Findings from this single high-yield patient demonstrate that the primary role of ZFPM2 in testicular development may be independent of SRY. This adds ZFPM2 to the brief (<10) list of genes capable of directing testicular development in the 46,XX context, absent SRY. Overall, new understanding of these genes demonstrates that the role of SRY as a "master regulator" of testicular development may be less than previously thought.


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