Oligogenic analysis across broad phenotypes of 46,XY differences in sex development associated with NR5A1/SF-1 variants: findings from the international SF1next study

• DOI: 10.1016/j.ebiom.2025.105624
• Publication Date: 2025-03-03T18:52:17Z
• Authors: Chrysanthi Kouri; Idoia Martinez de...; Rawda Naamneh-Elz...; Grit Sommer; Kay-Sara Sauter; Christa E. Flück; Saygin Abali; Zehra Yavas Abali; S. Faisal Ahmed; Leyla Akin; Maricruz Almaraz; Laura Audí; Murat Aydin; Antonio Balsamo; Federico Baronio; Jillian Bryce; Kanetee Busiah; Maria Caimari; Núria Camats-Tarr...; Ariadna Campos-Ma...; Luis Castaño; Anna Casteràs; Semra Çetinkaya; Hedi L. Claahsen ...; Martine Cools; Ines Costa; Fatma Feyza Daren...; Justin H. Davies; Isabel Esteva; Helena Fabbri-Sca...; Courtney A. Finla...; Emilio Garcia; Beatriz Garcia- C...; Alina German; Evgenia Globa; Gil Guerra-Junior; Julio Guerrero; Tulay Guran; Sabine E. Hannema; Olaf Hiort; Josephine Hirsch; Ieuan Hughes; Marco Janner; Uchenna Kennedy; Zofia Kolesinska; Katherine Lachlan; Anna Lauber-Biason; Jana Krenek Malikova; Dagmar L’Allemand; Nina Lenhnerr-Taube; Angela Lucas-Herald; Jamala Mammadova; Veronica Mericq; Isabel Mönig; Francisca Moreno; Julia Mührer; Marek Niedziela; Anna Nordenstrom; Burçe Orman; Sukran Poyrazoglu; Jose M. Rial; Meilan M. Rutter; Amaia Rodríguez; Tara Schafer-Kalk...; Sumudu Nimali Sen...; Maria Sredkova-Ru...; LIoyd J.W. Tack; Rieko Tadokoro-Cu...; Ajay Thankamony; Mónica Tomé; Amaia Vela; Malgorzata Wasnie...; David Zangen; Nataliya Zelinska

Oligogenic inheritance has been suggested as a possible mechanism to explain the broad phenotype observed in individuals with differences of sex development (DSD) harbouring NR5A1/SF-1 variants. We investigated genetic patterns oligogenicity cohort 30 variants and 46,XY DSD recruited from international SF1next study, using whole exome sequencing (WES) on family trios whenever available. WES data were analysed tailored filtering algorithm designed identify rare SF-1-related genes. Identified subsequently tested Resource for Variant Analysis (ORVAL) bioinformatics platform combined pathogenicity individual variant. In 73% (22/30) related DSD, we identified one seven additional variants, predominantly known DSD-related genes, that might contribute phenotype. found identical eight unrelated genes (e.g., TBCE, FLNB, GLI3 PDGFRA) different frequently associated CDH23, GLI2, KAT6B, MYO7A, PKD1, SPRY4 ZFPM2) 15 index cases. Our study also combinations novel candidate These findings highlight complex landscape NR5A1/SF-1, where several cases, use advanced testing specific algorithms machine learning tools revealed hits may Swiss National Science Foundation Boveri Zurich.