IDSD2026 Oral Communication Abstracts Session 1 (7 abstracts)
Exploring the underlying gene expression profiles of differences of sex development phenotypes through transcriptome analysis
Helena Fabbri-Scallet 1,2 , Verónica Calonga-Solís 3 , Gil Guerra-Júnior 2 , Maricilda Palandi de Mello 1 , Andréa Trevas Maciel-Guerra 4 , Márcio Lopes Miranda 5 , Arthur Antolini-Tavares 6 , Hauke Busch 7 , Axel Künstner 7 , Ralf Werner 8 & Olaf Hiort 8
1Center for Molecular Biology and Genetic Engineering, State University of Campinas, São Paulo, Brazil; 2Department of Pediatrics, Faculty of Medical Sciences, State University of Campinas, São Paulo, Brazil; 3Department of Biological Sciences, The University of North Carolina at Charlotte, Charlotte, NC, USA; 4Department of Medical Genetics and Genomics Medicine, School of Medical Sciences, University of Campinas, São Paulo, Brazil; 5Pediatric Surgery Department, School of Medical Sciences, State University of Campinas, São Paulo, Brazil; 6Departament of Pathology, School of Medical Sciences, State University of Campinas, São Paulo, Brazil; 7Medical Systems Biology Division, Lübeck Institute of Experimental Dermatology, University of Lübeck, 23562 Lübeck, Germany; 8Department of Paediatric and Adolescent Medicine, Division of Paediatric Endocrinology and Diabetes, University of Lübeck, Lübeck, Germany. Correspondence to: [email protected]
Background: Differences of sex development (DSD) comprise a heterogeneous group of conditions characterized by atypical chromosomal, gonadal, or anatomical sex. Although many genetic causes have been identified, the transcriptional programs that control human gonadal differentiation and their disruption in DSD remain poorly understood.
Methods: Bulk RNA sequencing was performed of gonadal tissue from 11 individuals with DSD and compared their transcriptomes to developmental stage–matched control gonads obtained from public datasets. Dimensionality reduction using curated sex-differentiation gene sets was applied to position samples along male–female transcriptional axes. Differential expression and pathway analyses were used to identify disrupted molecular programs, which were interpreted in the context of available histological and clinical data.
Results: DSD gonads did not cluster with typical male or female controls but instead occupied an intermediate transcriptional space, reflecting variable degrees of testicular and ovarian differentiation independent of chromosomal sex. Key sex-determining genes were not within the normal range, with reduced ovarian markers and altered expression of testis-associated genes. In 46,XY DSD samples, pathways related to spermatogenesis, cell cycle progression, and metabolism were broadly downregulated, consistent with impaired testicular development. Adult PGD cases showed transcriptional signatures of reduced mitotic activity and defective germ cell maturation, whereas prepubertal PGD samples retained expression of testis-maintaining factors such as DMRT1 and activation of developmental and proliferative pathways. In 46,XX OT-DSD samples, both testicular and ovarian gene networks were simultaneously active, in line with mixed histological phenotypes. Across all DSD groups, the epigenetic regulator CBX2 was consistently downregulated, suggesting a shared defect in stabilization of sex-specific regulatory programs.
Conclusion: Human gonadal fate in DSD is best described as a transcriptional spectrum rather than a binary outcome. Transcriptome profiling reveals molecular states that are not predicted by karyotype or external phenotype alone, highlighting the importance of RNA-based analyses for understanding the biology and clinical heterogeneity of DSD.
Volume 118
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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