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

Stefan John White, Thomas Ohnesorg, Amanda Notini, Kelly Roeszler, Jacqueline Hewitt, Hinda Daggag, Craig Smith, Erin Turbitt, Sonja Gustin, Jocelyn van den Bergen, Denise Miles, Patrick Western, Valerie Arboleda, Valerie Schumacher, Lavinia Gordon, Katrina Bell, Henrik Bengtsson, Terence Speed, John Hutson, Garry L WarneVincent Harley, Peter Koopman, Eric Vilain, Andrew Sinclair

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    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.
    Original languageEnglish
    Article number e17793
    Number of pages10
    JournalPLoS ONE
    Issue number3
    Publication statusPublished - 2011

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