Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort

Stefanie Eggers, Simon Sadedin, Jocelyn A. van den Bergen, Gorjana Robevska, Thomas Ohnesorg, Jacqueline Hewitt, Luke Lambeth, Aurore Bouty, Ingrid M. Knarston, Tiong Yang Tan, Fergus Cameron, George Werther, John Hutson, Michele O’Connell, Sonia R. Grover, Yves Heloury, Margaret Zacharin, Philip Bergman, Chris Kimber, Justin Brown, Nathalie Webb, Matthew F. Hunter, Shubha Srinivasan, Angela Titmuss, Charles F. Verge, David Mowat, Grahame Smith, Janine Smith, Lisa Ewans, Carolyn Shalhoub, Patricia Crock, Chris Cowell, Gary M. Leong, Makato Ono, Antony R. Lafferty, Tony Huynh, Uma Visser, Catherine S. Choong, Fiona McKenzie, Nicholas Pachter, Elizabeth M. Thompson, Jennifer Couper, Anne Baxendale, Jozef Gecz, Benjamin J. Wheeler, Craig Jefferies, Karen MacKenzie, Paul Hofman, Philippa Carter, Richard I. King, Csilla Krausz, Conny M. A. van Ravenswaaij-Arts, Leendert Looijenga, Sten Drop, Stefan Riedl, Martine Cools, Angelika Dawson, Achmad Zulfa Juniarto, Vaman Khadilkar, Anuradha Khadilkar, Vijayalakshmi Bhatia, Vũ Chí Dũng, Irum Atta, Jamal Raza, Nguyen thi Diem Chi, Tran Kiem Hao, Vincent Harley, Peter Koopman, Garry Warne, Sultana Faradz, Alicia Oshlack, Katie L. Ayers, Andrew H. Sinclair

Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously. We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46,XY DSD and 48 with 46,XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46,XY DSD. In patients with 46,XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management. Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes.