Endocrine Abstracts

Background: Differences of sex development (DSD) encompass a heterogeneous group of congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical. DSD have diverse genetic etiologies and overlapping phenotypes. Genetic testing is increasingly integrated into multidisciplinary DSD care, yet real-world diagnostic yield, testing strategies, and clinical impact remain variably characterized.

Methods: We performed a retrospective cohort study of 112 patients evaluated in a multidisciplinary DSD clinic over a 5-year period. Clinical data, referral characteristics, time to diagnosis, and genetic testing modalities were extracted through medical record review. Genetic diagnostic yield and clinical impact were analyzed.

Results: Genetic testing was pursued in 105 patients (93.8%), with an overall diagnostic yield of 45.7%. Yield varied significantly by karyotype, with higher yield among 46,XY patients compared to 46,XX patients (51.9% vs. 13.5%, P =0.0002). Diagnostic yield also differed by testing modality, with highest yields observed for targeted single-gene testing when a specific monogenic condition was suspected, followed by gene panel testing and exome sequencing. Among patients without a known diagnosis at referral who ultimately received a genetic diagnosis, the median time from referral to diagnostic confirmation was 4.4 months. Genetic testing directly informed or altered clinical management in 18.1% of patients (n = 19), including diagnostic clarification, modification of gonadectomy or hormone replacement recommendations, changes in surveillance for malignancy or multisystem disease, and changes in sex assignment within a multidisciplinary context.

Conclusions: Genetic testing plays a critical role in the evaluation and management of patients with DSD, with meaningful impact on diagnosis, counseling, and individualized care. Diagnostic yield varies by karyotype and testing modality, underscoring the need for karyotype-informed and phenotype-driven testing strategies and early integration of genetics expertise. Multidisciplinary DSD clinics facilitate timely diagnostic resolution and coordinated care. However, ongoing efforts to standardize testing algorithms, to address barriers to access, and to incorporate evolving genomic technologies and variant interpretation are needed to optimize outcomes. Based on our findings and clinical experience, we propose a genetic diagnostic algorithm for DSD that emphasizes karyotype- and phenotype-guided decision-making to inform the use of targeted vs broader genomic testing.