Differences of sex development: from gene discovery to clinically actionable genomics.

Abstract

Purpose of review: Differences of sex development (DSD) arise from disruptions in chromosomal, gonadal, or anatomical sex. Over the past 2 years, advances in sequencing technologies, enhancer biology, mitochondrial steroidogenesis, and sex-chromosome dosage effects have reshaped diagnostic and mechanistic understanding. This review synthesizes key discoveries and highlights their implications for clinical practice, including diagnostic pathways, endocrine surveillance, fertility counseling, and tumor-risk stratification.

Recent findings: Diagnostic yield in 46,XY DSD remains below 50% with gene panels, driving adoption of whole-exome, whole-genome, and long-read sequencing to detect regulatory, structural, and other complex genetic mechanisms. New insights include enhancer-driven sex reversal, topologically associating domains disruption, and oligogenicity in NR5A1 /SF1-related DSD. Mechanistic studies clarify roles for NR2F2 in Leydig lineage specification, mitochondrial genes in steroidogenesis, and X-chromosome dosage effects in germ cell maturation. Clinically, genomic findings increasingly improve our understanding for adrenal and gonadal function, fertility potential, and tumor risk, while supporting individualized gonadal management and shared decision-making.

Summary: DSD genetics is transitioning from single-gene models to integrated, multilayered pathomechanisms. Early comprehensive genomic testing, functional interpretation of regulatory and structural variations, and assessment of epigenetic and mitochondrial mechanisms, will be essential for improving diagnostic yield and delivering precise, ethically grounded care in DSD.