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Reproductive Endocrinology

SUN-128 - Cellular Heterogeneity and Lineage Misalignment in Disorders of Sex Development via Single-Nucleus Transcriptomics

Sunday, June 14, 2026
9:00 AM - 4:00 PM CT
Location: ENDOExpo; Poster Floor
Disclosure(s):
Ja Hye Kim, MD and PhD: No financial relationships to disclose


Background: Disorders of Sex Development (DSD) exhibit high clinical and genetic heterogeneity, making it challenging to pinpoint the exact molecular mechanisms of gonadal dysfunction. This study aims to elucidate the cell-specific transcriptional landscapes and regulatory networks underlying impaired gonadogenesis in DSD patients with distinct genotypes.

Methods: We performed single-nucleus RNA sequencing (snRNA-seq) on gonadal tissues from three DSD patients: 46,XX ovotesticular DSD (DSD1), 46,XY DSD with a NR5A1 mutation (DSD2), and 46,XY congenital lipoid adrenal hyperplasia with STAR mutations (DSD3). Advanced computational pipelines were utilized to analyze cellular composition, lineage-specific gene expression, and transcription factor activity.

Results: snRNA-seq identified highly patient-specific cellular environments. In DSD1 (46,XX), we observed impaired somatic differentiation driven by an aberrant NR2F2-DCN axis in Sertoli and Leydig cells. DSD2 (46,XY, NR5A1) showed significant fibroblast heterogeneity and a degenerating Leydig-like subpopulation associated with steroidogenic failure. DSD3 (46,XY, STAR) was characterized by the complete absence of Sertoli cells and the presence of transcriptionally abnormal spermatid-like clusters, indicating severe disruption of the testicular niche.

Conclusions: Our findings reveal that DSD pathogenesis is driven by lineage misalignment and dysregulated maturation states of somatic cells. The identification of the NR2F2–DCN pathway as a key factor in impaired development suggests new diagnostic markers. This study demonstrates that single-cell resolution analysis is crucial for understanding the achieving precision mechanisms in DSDs.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*