The evolution and clinical predictors of molecular findings in 46XY DSD patients: experience from a single multidisciplinary centre

Yana Deyanova; Malika Alimussina; Angela Lucas-Herald; Sophie Longmuir; Frank Amy R; McNeilly Jane D; Violeta Iotova; Ahmed S Faisal; Ruth McGowan

doi:10.1530/endoabs.118.PO9

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Endocrine Abstracts (2026) 118 PO9 | DOI: 10.1530/endoabs.118.PO9

IDSD2026 Poster Abstracts Poster Abstracts (93 abstracts)

The evolution and clinical predictors of molecular findings in 46XY DSD patients: experience from a single multidisciplinary centre

Yana Deyanova ^1,2 , Malika Alimussina ¹ , Angela Lucas-Herald ¹ , Sophie Longmuir ³ , Amy R Frank ⁴ , Jane D McNeilly ⁵ , Violeta Iotova ² , S Faisal Ahmed ¹ & Ruth McGowan ^1,3

Author affiliations

¹Developmental Endocrinology Research Group, University of Glasgow, Royal Hospital for Children, Glasgow, United Kingdom; ²Department of Paediatrics, Medical University of Varna, Bulgaria; ³West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow, UK; ⁴Department of Clinical Biochemistry, Glasgow Royal Infirmary, Glasgow, UK; ⁵Department of Clinical Biochemistry, Royal Hospital for Children, Glasgow, UK

Introduction: 46XY disorders of sex development (DSD) are rare genetic conditions presenting with a nonspecific phenotype. Molecular diagnosis is a cornerstone of clinical care.

Objectives: To assess the clinical/biochemical profile in patients with 46XY DSD, the diagnostic yield of applied genetic panel and correlations between phenotype and genetic results.

Methods: Retrospective clinical data was collected for patients with suspected 46XY DSD from West of Scotland who underwent next generation sequencing (NGS) of 56 DSD-associated genes or a single gene of interest in Glasgow between 2018-2025. Genetic variants were classified according to ACGM guidelines. Chi-square test was performed for correlation analysis.

Results: In the 165 eligible patients, median age at presentation, genetic request and genetic report was 1.0, 3.3, and 3.9 years, respectively. The most common presenting phenotypes were complex genital abnormalities (34.5%), isolated undescended testes (27.3%) and isolated hypospadias (26.7%). EMS was available for 159 patients with severe, moderate or mild/no undervirilization in 56 (35.2%), 56 (35.2%), and 47 (29.6%), respectively. Endocrine assessment of testosterone, gonadotrophin and AMH levels was available for 163 patients and revealed no abnormalities in 117 (71.8%), and one, two or three abnormal results in 23 (14.1%), 17 (10.4%) and 6 (3.7%) patients, respectively. Genetic result was normal in 124 patients. A total of 53 variants were identified in 41 (24.8%) patients - 40 variants of unknown significance (VUS) in 20% and 13 pathogenic/likely pathogenic (P/LP) variants in 7% of the patients. The presence of a P/LP variant correlated with a higher number of biochemical abnormalities (P =0.001) and lower EMS (P =0.02). There was no correlation between EMS and presence of biochemical abnormalities (P =0.354). Over the 8-year period, the patients with a higher EMS undergoing genetic analysis increased and the proportion of cases of reported variants decreased.

Conclusions: Patients with a higher number of biochemical abnormalities and lower EMS were more likely to have a P/LP variant but some patients with normal biochemistry also had a P/LP variant. The lower number of positive genetics results in recent years may be attributed to stricter reporting criteria from 2020 onwards, and to testing patients with milder phenotype.