IMPE2023 Free Communications Endocrinology of Sex Differences 2 (4 abstracts)
Uncovering the role of the SF-1/NR5A1 p.Gly146Ala variant for the phenotype of DSD patients
Idoia Martinez de Lapiscina 1,2 , Chrysanthi Kouri 3 , Josu Aurrekoetxea 4 , Mirian Sanchez 5 , Rawda Naamneh 3 , Grit Sommer 1 , Kay Sauter 1 , Nuria Camats 6 , Gema Grau 7 , Itxaso Rica 7 , Amaia Rodriguez 8 , Amaia Vela 7 , Alicia Cortazar 9 , M Concepción Alonso 10 , Pilar Bahillo 11 , Laura Berthod 12 , Isabel Esteva 13 , Luis Castaño 7 & Christa E Flück 1
1Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, Department for BioMedical Research, University of Bern, Bern, Switzerland. 2Research into the genetics and control of diabetes and other endocrine disorders, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, University of the Basque Country (UPV-EHU), CIBERDEM, CIBERER, ISCIII, Endo-ERN, Barakaldo, Spain. 3Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, Department for BioMedical Research, Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland. 4Research group of Medical Oncology, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, University of the Basque Country (UPV-EHU), Barakaldo, Spain. 5Research into the genetics and control of diabetes and other endocrine disorders, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo, Spain. 6Growth and Development group, Vall d'Hebron Research Institute (VHIR), Hospital Universitari Vall d'Hebron, CIBERER, ISCIII, Barcelona, Spain. 7Department of Pediatric Endocrinology, Cruces University Hospital. Research into the genetics and control of diabetes and other endocrine disorders, Biocruces Bizkaia Health Research Institute, University of the Basque Country (UPV-EHU), CIBERDEM, CIBERER, ISCIII, Endo-ERN, Barakaldo, Spain. 8Department of Pediatric Endocrinology, Cruces University Hospital. Research into the genetics and control of diabetes and other endocrine disorders, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain. 9Endocrinology Department, Cruces University Hospital, CIBERDEM, ISCIII, Barakaldo, Spain. 10La Princesa University Hospital, Madrid, Spain. 11Department of Pediatrics, University Hospital of Valladolid, Valladolid, Spain. 12Pediatric Endocrinology Department, Marques de Valdecilla University Hospital, Santander, Spain. 13Endocrinology Section, Gender Identity Unit, Regional University Hospital of Malaga, Malaga, Spain
Background and Aim: The SF-1/NR5A1 variant c.437G>C/p.Gly146Ala is common among individuals with disorders/differences of sex development (DSD). It has been considered a polymorphism due to its high allele frequency in the control population (23.5%, gnomAD) and its lack of negative effect in cell-based studies. However, its possible role as a disease modifier is still unclear given that oligogenic inheritance has been described in patients with SF1/NR5A1 gene variants. In this study, we therefore performed a broader genetic screening in DSD individuals carrying the SF-1/NR5A1 p.Gly146Ala variant for other DSD-causing variants in order to clarify the role of a SF1/NR5A1 p.Gly146Ala variant for the phenotype of these carriers.
Methods: We studied 14 paediatric DSD individuals with the p.Gly146Ala variant in the SF-1/NR5A1 gene who are part of a larger DSD cohort from the Biocruces Bizkaia Health Research Institute in Spain. DSD individuals were screened via whole-exome sequencing (WES) and analysed with a specific data filtering algorithm to detect variants in SF-1/NR5A1- and DSD-related genes or through a targeted DSD-gene panel. We used several in silico tools to predict the impact of gene variants and searched for reported disease-causing variants in literature and the HGMD and ClinVar databases. Variants were classified according to the ACMG guidelines for pathogenicity.
Results: The phenotype of the individuals (10/14 46,XY, 4/14 46,XX) ranged from scrotal hypospadias and ambiguous genitalia in 46,XY DSD to typical male external genitalia and ovotestes in 46,XX DSD patients. Patients were African (8/14), Spanish (4/14) and Asian (2/14). Five patients were homozygous and nine heterozygous for p.Gly146Ala. In ten subjects we found either a clear DSD gene variant (e.g. in AR, LHCGR) or one to three potentially deleterious variants that could explain the phenotype alone (e.g. in FGFR3, CHD7, ADAMTS16).
Conclusion: Our study shows that most individuals carrying the p.Gly146Ala SF1/NR5A1 variant, harbour at least one other deleterious gene variant which can explain the DSD phenotype alone, when evaluated with a broader genetic approach. This finding suggest that the p.Gly146Ala variant may not contribute to the pathogenesis of DSD and qualifies as a benign polymorphism. Individuals, in whom the p.Gly146Ala SF-1/NR5A1 gene variant has been identified alone need to be re-evaluated with advanced NGS methods.
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