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

Eggers, Stefanie, Sadedin, Simon, van den Bergen, Jocelyn A., Robevska, Gorjana, Ohnesorg, Thomas, Hewitt, Jacqueline, Lambeth, Luke, Bouty, Aurore, Knarston, Ingrid M., Tan, Tiong Yang, Cameron, Fergus, Werther, George, Hutson, John, O'Connell, Michele, Grover, Sonia R., Heloury, Yves, Zacharin, Margaret, Bergman, Philip, Kimber, Chris, Brown, Justin, Webb, Nathalie, Hunter, Matthew F., Srinivasan, Shubha, Titmuss, Angela, Verge, Charles F., Mowat, David, Smith, Grahame, Smith, Janine, Ewans, Lisa, Shalhoub, Carolyn, Crock, Patricia, Cowell, Chris, Leong, Gary M., Ono, Makato, Lafferty, Antony R., Huynh, Tony, Visser, Uma, Choong, Catherine S., McKenzie, Fiona, Pachter, Nicholas, Thompson, Elizabeth M., Couper, Jennifer, Baxendale, Anne, Gecz, Jozef, Wheeler, Benjamin J., Jefferies, Craig, MacKenzie, Karen, Hofman, Paul, Carter, Philippa, King, Richard I., Krausz, Csilla, van Ravenswaaij-Arts, Conny M. A., Looijenga, Leendert, Drop, Sten, Riedl, Stefan, Cools, Martine, Dawson, Angelika, Juniarto, Achmad Zulfa, Khadilkar, Vaman, Khadilkar, Anuradha, Bhatia, Vijayalakshmi, Dung, Vũ Chí, Atta, Irum, Raza, Jamal, Thi Diem Chi, Nguyen, Hao, Tran Kiem, Harley, Vincent, Koopman, Peter, Warne, Garry, Faradz, Sultana, Oshlack, Alicia, Ayers, Katie L. and Sinclair, Andrew H. (2016) Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort. Genome Biology, 17 1: . doi:10.1186/s13059-016-1105-y

Author Eggers, Stefanie
Sadedin, Simon
van den Bergen, Jocelyn A.
Robevska, Gorjana
Ohnesorg, Thomas
Hewitt, Jacqueline
Lambeth, Luke
Bouty, Aurore
Knarston, Ingrid M.
Tan, Tiong Yang
Cameron, Fergus
Werther, George
Hutson, John
O'Connell, Michele
Grover, Sonia R.
Heloury, Yves
Zacharin, Margaret
Bergman, Philip
Kimber, Chris
Brown, Justin
Webb, Nathalie
Hunter, Matthew F.
Srinivasan, Shubha
Titmuss, Angela
Verge, Charles F.
Mowat, David
Smith, Grahame
Smith, Janine
Ewans, Lisa
Shalhoub, Carolyn
Crock, Patricia
Cowell, Chris
Leong, Gary M.
Ono, Makato
Lafferty, Antony R.
Huynh, Tony
Visser, Uma
Choong, Catherine S.
McKenzie, Fiona
Pachter, Nicholas
Thompson, Elizabeth M.
Couper, Jennifer
Baxendale, Anne
Gecz, Jozef
Wheeler, Benjamin J.
Jefferies, Craig
MacKenzie, Karen
Hofman, Paul
Carter, Philippa
King, Richard I.
Krausz, Csilla
van Ravenswaaij-Arts, Conny M. A.
Looijenga, Leendert
Drop, Sten
Riedl, Stefan
Cools, Martine
Dawson, Angelika
Juniarto, Achmad Zulfa
Khadilkar, Vaman
Khadilkar, Anuradha
Bhatia, Vijayalakshmi
Dung, Vũ Chí
Atta, Irum
Raza, Jamal
Thi Diem Chi, Nguyen
Hao, Tran Kiem
Harley, Vincent
Koopman, Peter
Warne, Garry
Faradz, Sultana
Oshlack, Alicia
Ayers, Katie L.
Sinclair, Andrew H.
Title Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort
Journal name Genome Biology   Check publisher's open access policy
ISSN 1474-760X
Publication date 2016-11-29
Sub-type Article (original research)
DOI 10.1186/s13059-016-1105-y
Open Access Status DOI
Volume 17
Issue 1
Total pages 21
Place of publication London, United Kingdom
Publisher BioMed Central
Language eng
Formatted abstract
Background: 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.

Results: 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.

Conclusions: 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.
Keyword Cohort
Disorders of sex development
Genetic diagnosis
Massively parallel sequencing
Targeted gene panel
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
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