Martínez de LaPiscina, IdoiaIdoiaMartínez de LaPiscinaMahmoud, Rana AaRana AaMahmoudSauter, Kay-SaraKay-SaraSauterEsteva, IsabelIsabelEstevaAlonso, MilagrosMilagrosAlonsoCosta, InesInesCostaRial-Rodriguez, Jose ManuelJose ManuelRial-RodriguezRodríguez-Estévez, AmaiaAmaiaRodríguez-EstévezVela, AmaiaAmaiaVelaCastano, LuisLuisCastanoFlück Pandey, Christa EmmaChrista EmmaFlück Pandey0000-0002-4568-55042024-10-052024-10-052020-11-13https://boris-portal.unibe.ch/handle/20.500.12422/55908Variants of NR5A1 are often found in individuals with 46,XY disorders of sex development (DSD) and manifest with a very broad spectrum of clinical characteristics and variable sex hormone levels. Such complex phenotypic expression can be due to the inheritance of additional genetic hits in DSD-associated genes that modify sex determination, differentiation and organ function in patients with heterozygous NR5A1 variants. Here we describe the clinical, biochemical and genetic features of a series of seven patients harboring monoallelic variants in the NR5A1 gene. We tested the transactivation activity of novel NR5A1 variants. We additionally included six of these patients in a targeted diagnostic gene panel for DSD and identified a second genetic hit in known DSD-causing genes STAR, AMH and ZFPM2/FOG2 in three individuals. Our study increases the number of NR5A1 variants related to 46,XY DSD and supports the hypothesis that a digenic mode of inheritance may contribute towards the broad spectrum of phenotypes observed in individuals with a heterozygous NR5A1 variation.enAMH DSD FOG2 NR5A1/SF1 STAR disorder/difference of sex development genotype–phenotype correlation oligogenic disorders steroidogenic factor 1600 - Technology::610 - Medicine & health500 - Science::570 - Life sciences; biologyarticle10.48350/1504073320280210.3390/ijms21228554