ECEESPE2025 Poster Presentations Reproductive and Developmental Endocrinology (93 abstracts)
Oligogenicity associated with the adrenal phenotype of individuals with NR5A1/SF-1 variants
Idoia Martinez de LaPiscina 1 , Kay Sara Sauter 1 , Chrysanthi Kouri 1 , Rawda Naamneh-Elzenaty 1 , Antonio Balsamo 2 , Federico Baronio 3 , Kanetee Busiah 4 , Semra Çetinkaya 5 , Jana Krenek Malikova 6 & Christa Flück 1
1Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. Department for BioMedical Research, University of Bern, Bern, Switzerland. Research into the genetics and control of diabetes and other endocrine disorders, Biobizkaia Health Research Institute, Cruces University Hospital, Barakaldo, Spain. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain. CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. Endo-ERN, Amsterdam, The Netherlands., Bern, Switzerland; 2Researcher of Alma Mater Studiorum, S. Orsola-Malpighi, University Hospital, Bologna, Italy., Bologna, Italy; 3Department of Medical and Surgical Sciences, IRCCS S. Orsola-Malpighi, University Hospital, Bologna, Italy., Bologna, Italy; 4Paediatric Endocrinology, Diabetology and Obesity Unit, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland, Lausanne, Switzerland; 5University of Health Sciences Turkey, Ankara, Turkey, Clinic of Pediatric Endocrinology, Dr. Sami Ulus, Obstetrics and Pediatrics Training and Research Hospital, Ankara, Turkey, Ankara, Türkiye; 6Department of Paediatrics, Second Faculty of Medicine of Charles University and University Hospital Motol, Prague, Czech Republic, Prague, Czech Republic
JOINT1441
Background: NR5A1/SF-1 variants cause differences of sex development (DSD) and manifest with a broad phenotype. Many individuals with DSD and NR5A1/SF-1 variants have anomalies in other organs, predominantly the spleen, rarely the adrenals. Oligogenicity could contribute to the variable phenotype. This study aimed at investigating individuals with NR5A1/SF-1 variants presenting with DSD and adrenal anomalies for additional genetic variants that may promote their exclusive adrenal phenotype.
Methods: Within the framework of the SF1next study, we had four patients with a DSD phenotype and adrenal anomalies. These individuals were investigated by whole exome sequencing (WES); after filtering, variants were classified according ACMG guidelines for pathogenicity assessment. Of patient 3 (Table1) and a healthy donor, we differentiated human fibroblasts-derived induced pluripotent stem cells (iPSCs) into adrenal-like cells (iALC) and assessed the model by liquid chromatography–mass spectrometry (LC-MS). Analysis of the transcriptome (RNA-seq) was performed to compare differentially expressed genes (DEG) between NR5A1/SF-1 mutant and wild-type (wt) iALC.
Results: Table1 summarizes the phenotypic and genetic characteristics of the four patients. Besides the NR5A1/SF-1 variants, we found additional (likely) causative variants in NNT and CDKN1C genes with established involvement in adrenal disorders in two patients. In the other two patients, filtering revealed one potentially deleterious variant in ADCY1 and ABLIM3, respectively. RNAseq showed that expression levels of 1480 genes were significantly different (up or downregulated) in the mutant NR5A1/SF-1 in comparison to wt when investigated within the background context of patient and control-derived iALCs. We observed higher expression levels of NR5A1/SF-1 in mutant than in wt iALC, while ABLIM3 expression levels were similar across samples.
| Patient (Karyotype) | DSD phenotype; adrenal anomaly | Other anomalies | Genetic findings (zygosity) |
| 1 (46,XY) | Opposite sex; adrenal insufficiency | NR5A1, p.(R427W) (hom) CDKN1C, p.(A202_P205del) (het); ABLIM3, p.(L555Q) (het) | |
| 2 (46,XY) | Severe; adrenal insufficiency | NR5A1, p.[(E7Ter);(T296M)] (comp het) ADCY1, (p.L719Q) (het); SULT2B1, (p.G187R) (het) | |
| 3 (46,XX) | Typical; adrenal hypoplasia | Asplenia | NR5A1, p.(R92Q) (hom) ABLIM3, p.(L649Q) (het) |
| 4 (46,XY) | Severe; partial adrenal insufficiency | Polysplenia | NR5A1, p.(P14CfsTer19) (het) NNT, p.(R693H) (het) |
Conclusion: Our study indicates that individuals with DSD and rare adrenal anomalies who have NR5A1/SF-1 variants, harbor other deleterious gene variants that may explain their adrenal phenotype. Thus, variants in NR5A1/SF-1 may not suffice to cause an adrenal phenotype. Our in-vitro model is a potent tool to study adrenal anomalies and the molecular effects of novel genes proposed to be disease-causing.
Volume 110
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Endocrine Abstracts
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