IDSD2026 Poster Abstracts Poster Abstracts (93 abstracts)
Broad spectrum of DSD with NR5A1 variants: challenges to address/confirm mechanisms of variable expressivity and incomplete penetrance
Chrysanthi Kouri 1,2 , Kay-Sara Sauter 1,2 , Kanetee Busiah 3 , Tulay Güran 4 , Uchenna Kennedy 5 , Nina Lenherr-Taube 6 , Idoia Martinez de LaPiscina 1,2,7,8,9 , Julia Rohayem 10 , Ajay Thankamony 11 , Amaia Vela 6,7,8,12,13 & Christa E. Flück 1,2
1Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; 2Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland; 3Paediatric Endocrinology, Diabetology and Obesity Unit, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland; 4Department of Paediatric Endocrinology and Diabetes, Marmara University, School of Medicine, 34841 Istanbul, Turkey; 5Department of Pediatric Urology, University Children’s Hospital Zurich, Zurich, Switzerland; 6Division of Pediatric Endocrinology and Diabetology, University Children’s Hospital Zurich, University of Zurich, Zurich, Switzerland; 7Research into the Genetics and Control of Diabetes and Other Endocrine Disorders, Biobizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Spain; 8CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid 28029, Spain; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid 28029, Spain.; 9Endo-ERN, Amsterdam 1081 HV, the Netherlands; 10Children’s Hospital of Easter Switzerland, Paediatric Endocrinology and Diabetology, St. Gallen, Switzerland; 11Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, United Kingdom; 12Department of Paediatric Endocrinology, Cruces University Hospital, 48903 Barakaldo, Spain; 13Faculty of Medicine and Dentistry, University of the Basque Country (EHU), 48903 Leioa, Spain. Correspondence to: [email protected]
Background: NR5A1 (SF 1) is a key transcription factor essential for gonadal and adrenal development, and pathogenic variants are a major cause of 46,XY/46,XX differences of sex development (DSD). Despite extensive case series, the broad phenotypic spectrum remains difficult to explain. This has raised interest in mechanisms contributing to variable expressivity and incomplete penetrance, including genetic, epigenetic and regulatory influences, transcript or protein level effects and environmental factors. Many of these are likely tissue specific or dependent on developmental timing, requiring biological material that is often unavailable. We therefore investigated NR5A1 expression in blood from individuals with heterozygous NR5A1 variants (DSD subjects and asymptomatic carriers) and from wild type controls, to assess whether NR5A1 expression differs in blood, and whether blood is suitable for mechanistic studies.
Methods: We investigated six unrelated families with NR5A1 variants, who provided blood samples. Total RNA was extracted from EDTA blood (Zymo-Kit Whole Blood), converted to cDNA, and NR5A1 transcript levels were quantified by qPCR using gene specific primers. Clinical information, including DSD severity, was provided in pseudo anonymised form by the clinicians. For each family, we documented variant inheritance, and the phenotypic range among affected individuals and carriers.
Results: Across the six families, individuals carrying NR5A1 variants displayed variable clinical presentations, from asymptomatic carriers to those with mild or mild or pronounced phenotypic variations. The variants included missense, nonsense, and frameshift changes, frequently inherited from minimally affected relatives. Despite this variability, NR5A1 expression in blood was uniformly low across all groups. qPCR analyses showed no meaningful differences between affected individuals, asymptomatic carriers, and wild type relatives. High Ct values confirmed that NR5A1 is a low abundance transcript in blood, and expression levels did not vary within or between families.
Conclusions: NR5A1 expression in blood is uniformly low and does not correlate with genotype or the clinical severity of DSD in individuals carrying heterozygous NR5A1 variants. These findings indicate that blood is not a suitable surrogate tissue for investigating NR5A1–related mechanisms underlying phenotypic variability. Mechanistic studies will require access to tissues or model systems in which NR5A1is more robustly expressed and biologically relevant, particularly those reflecting gonadal or adrenal developmental contexts.
Volume 118
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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