Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis

White, Stefan, Ohnesorg, Thomas, Notini, Amanda, Roeszler, Kelly, Hewitt, Jacqueline, Daggag, Hinda, Smith, Craig, Turbitt, Erin, Gustin, Sonja, van den Bergen, Jocelyn, Miles, Denise, Western, Patrick, Arboleda, Valerie, Schumacher, Valerie, Gordon, Lavinia, Bell, Katrina, Bengtsson, Henrik, Speed, Terry, Hutson, John, Warne, Garry, Harley, Vincent, Koopman, Peter, Vilain, Eric and Sinclair, Andrew (2011) Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis. PLoS One, 6 3: e17793.1-e17793.10. doi:10.1371/journal.pone.0017793

Author White, Stefan
Ohnesorg, Thomas
Notini, Amanda
Roeszler, Kelly
Hewitt, Jacqueline
Daggag, Hinda
Smith, Craig
Turbitt, Erin
Gustin, Sonja
van den Bergen, Jocelyn
Miles, Denise
Western, Patrick
Arboleda, Valerie
Schumacher, Valerie
Gordon, Lavinia
Bell, Katrina
Bengtsson, Henrik
Speed, Terry
Hutson, John
Warne, Garry
Harley, Vincent
Koopman, Peter
Vilain, Eric
Sinclair, Andrew
Title Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2011-03-01
Year available 2011
Sub-type Article (original research)
DOI 10.1371/journal.pone.0017793
Open Access Status DOI
Volume 6
Issue 3
Start page e17793.1
End page e17793.10
Total pages 10
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Language eng
Subject 1300 Biochemistry, Genetics and Molecular Biology
1100 Agricultural and Biological Sciences
Abstract Disorders of sex development (DSD), ranging in severity from mild genital abnormalities to complete sex reversal, represent a major concern for patients and their families. DSD are often due to disruption of the genetic programs that regulate gonad development. Although some genes have been identified in these developmental pathways, the causative mutations have not been identified in more than 50% 46,XY DSD cases. We used the Affymetrix Genome-Wide Human SNP Array 6.0 to analyse copy number variation in 23 individuals with unexplained 46,XY DSD due to gonadal dysgenesis (GD). Here we describe three discrete changes in copy number that are the likely cause of the GD. Firstly, we identified a large duplication on the X chromosome that included DAX1 (NR0B1). Secondly, we identified a rearrangement that appears to affect a novel gonad-specific regulatory region in a known testis gene, SOX9. Surprisingly this patient lacked any signs of campomelic dysplasia, suggesting that the deletion affected expression of SOX9 only in the gonad. Functional analysis of potential SRY binding sites within this deleted region identified five putative enhancers, suggesting that sequences additional to the known SRY-binding TES enhancer influence human testis-specific SOX9 expression. Thirdly, we identified a small deletion immediately downstream of GATA4, supporting a role for GATA4 in gonad development in humans. These CNV analyses give new insights into the pathways involved in human gonad development and dysfunction, and suggest that rearrangements of non-coding sequences disturbing gene regulation may account for significant proportion of DSD cases. © 2011 White et al.
Keyword Determination reveals
Sry-related gene
Campomelic dysplasia
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 334314
Institutional Status UQ
Additional Notes Article number e17793

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
Institute for Molecular Bioscience - Publications
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Created: Sun, 27 Mar 2011, 10:02:35 EST