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<p>46,XY Differences of Sex Development (DSD) present major diagnostic challenges in consanguineous populations like Egypt, where genetic causes remain poorly characterized despite high prevalence. This study investigates the molecular spectrum and regional epidemiology of 46,XY DSD in Egypt to identify novel variants and improve diagnosis. Thirty-seven Egyptian patients with 46,XY DSD underwent clinical evaluation and hormonal profiling. We performed targeted genetic sequencing of key genes (<i>SRD5A2</i>,<i> AR</i>,<i> HSD17B3</i>,<i> NR5A1</i>,<i> SRY</i>,<i> and WT1</i>), and exome sequencing (ES) for cases that remained undiagnosed. We also reviewed previously reported Egyptian cases to build a comprehensive picture of the genetic landscape. Molecular diagnosis was achieved in 67% (25/37) of patients, including eleven novel variants in <i>AR</i>,<i> SRD5A2</i>,<i> HSD17B3</i>, and <i>ZNRF3</i>. Combining with prior data (<i>n</i> = 113), 5α-reductase deficiency was most frequent (52%), followed by AIS (23%) and 17β-HSDD (12%). Consanguinity was high (69%), with regional clustering in Upper Egypt and Sinai. Diagnostic delays were prominent in CAIS and 17β-HSDD cases. This study identified eleven novel pathogenic variants and provided further evidence implicating <i>ZNRF3</i> as a candidate gene in Egyptian 46,XY DSD patients. We confirmed 5α-reductase deficiency (52%) as the predominant etiology and demonstrated that ES significantly improves diagnostic yield. Key challenges included limited LC-MS/MS availability for steroid profiling and regional disparities in diagnostic resources. Future efforts should prioritize ES implementation and multicenter collaborations to address diagnostic delays.</p>

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Characterizing 46,XY Differences of Sex Development: Novel Genetic Variants and Diagnostic Pitfalls in a Single-Center Cohort

  • 期刊论文

  • 发表日期：

    2026年3月27日

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  • Heba Amin Hassan,
  • Mona Essawi,
  • Aya Elaidy,
  • Noura Eissa,
  • Mona Mekkawy,
  • Alaa Kamel,
  • Inas Mazen

摘要

46,XY Differences of Sex Development (DSD) present major diagnostic challenges in consanguineous populations like Egypt, where genetic causes remain poorly characterized despite high prevalence. This study investigates the molecular spectrum and regional epidemiology of 46,XY DSD in Egypt to identify novel variants and improve diagnosis. Thirty-seven Egyptian patients with 46,XY DSD underwent clinical evaluation and hormonal profiling. We performed targeted genetic sequencing of key genes (SRD5A2, AR, HSD17B3, NR5A1, SRY, and WT1), and exome sequencing (ES) for cases that remained undiagnosed. We also reviewed previously reported Egyptian cases to build a comprehensive picture of the genetic landscape. Molecular diagnosis was achieved in 67% (25/37) of patients, including eleven novel variants in AR, SRD5A2, HSD17B3, and ZNRF3. Combining with prior data (n = 113), 5α-reductase deficiency was most frequent (52%), followed by AIS (23%) and 17β-HSDD (12%). Consanguinity was high (69%), with regional clustering in Upper Egypt and Sinai. Diagnostic delays were prominent in CAIS and 17β-HSDD cases. This study identified eleven novel pathogenic variants and provided further evidence implicating ZNRF3 as a candidate gene in Egyptian 46,XY DSD patients. We confirmed 5α-reductase deficiency (52%) as the predominant etiology and demonstrated that ES significantly improves diagnostic yield. Key challenges included limited LC-MS/MS availability for steroid profiling and regional disparities in diagnostic resources. Future efforts should prioritize ES implementation and multicenter collaborations to address diagnostic delays.