Approach to Disorders of Sex Development in the Genomic Era

Area of Science:

• Genetics
• Endocrinology
• Developmental Biology

Background:

• Disorders of Sex Development (DSD) involve congenital discrepancies in chromosomal, gonadal, or anatomic sex.
• DSDs are classified by karyotype (46,XX, 46,XY, sex chromosomal).
• While 46,XX DSD is often linked to congenital adrenal hyperplasia, 46,XY DSD genetics are complex, involving over 100 genes.

Purpose of the Study:

• To review genetic mechanisms underlying DSD.
• To discuss various genetic testing modalities, their indications, prerequisites, and limitations.
• To outline an algorithmic approach for genetic diagnosis in DSD.

Main Methods:

• Review of genetic mechanisms and testing modalities for DSD.
• Discussion of next-generation sequencing (NGS) and chromosomal microarray (CMA) in DSD diagnosis.
• Presentation of an algorithmic approach to genetic diagnosis.

Main Results:

• Precise genetic diagnosis in DSD ends the diagnostic odyssey and aids in predicting outcomes.
• Advanced genetic testing (NGS, CMA) achieves precise diagnosis in 40-50% of 46,XY DSD cases.
• Genetic testing has limitations including cost, complex data analysis, variants of uncertain significance (VUS), and potential for negative results.

Conclusions:

• Genetic testing is crucial for diagnosing DSD, guiding management of gender development, puberty, and extragenital features.
• Test selection should balance diagnostic yield and cost, guided by clinical phenotype.
• Genetic testing for DSD requires pre-test counseling and collaboration with pediatric endocrinologists and geneticists.