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 Warne & 4 others Vincent Harley, Peter Koopman, Eric Vilain, Andrew Sinclair

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    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.
    Original languageEnglish
    Article number e17793
    Number of pages10
    JournalPLoS ONE
    Volume6
    Issue number3
    DOIs
    Publication statusPublished - 2011

    Cite this

    White, S. J., Ohnesorg, T., Notini, A., Roeszler, K., Hewitt, J., Daggag, H., ... Sinclair, A. (2011). Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis. PLoS ONE, 6(3), [ e17793]. https://doi.org/10.1371/journal.pone.0017793
    White, Stefan John ; 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, Terence ; Hutson, John ; Warne, Garry L ; Harley, Vincent ; Koopman, Peter ; Vilain, Eric ; Sinclair, Andrew. / Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis. In: PLoS ONE. 2011 ; Vol. 6, No. 3.
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    title = "Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis",
    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.",
    author = "White, {Stefan John} and Thomas Ohnesorg and Amanda Notini and Kelly Roeszler and Jacqueline Hewitt and Hinda Daggag and Craig Smith and Erin Turbitt and Sonja Gustin and {van den Bergen}, Jocelyn and Denise Miles and Patrick Western and Valerie Arboleda and Valerie Schumacher and Lavinia Gordon and Katrina Bell and Henrik Bengtsson and Terence Speed and John Hutson and Warne, {Garry L} and Vincent Harley and Peter Koopman and Eric Vilain and Andrew Sinclair",
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    White, SJ, Ohnesorg, T, Notini, A, Roeszler, K, Hewitt, J, Daggag, H, Smith, C, Turbitt, E, Gustin, S, van den Bergen, J, Miles, D, Western, P, Arboleda, V, Schumacher, V, Gordon, L, Bell, K, Bengtsson, H, Speed, T, Hutson, J, Warne, GL, Harley, V, Koopman, P, Vilain, E & Sinclair, A 2011, 'Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis', PLoS ONE, vol. 6, no. 3, e17793. https://doi.org/10.1371/journal.pone.0017793

    Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis. / White, Stefan John; 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, Terence; Hutson, John; Warne, Garry L; Harley, Vincent; Koopman, Peter; Vilain, Eric; Sinclair, Andrew.

    In: PLoS ONE, Vol. 6, No. 3, e17793, 2011.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis

    AU - White, Stefan John

    AU - Ohnesorg, Thomas

    AU - Notini, Amanda

    AU - Roeszler, Kelly

    AU - Hewitt, Jacqueline

    AU - Daggag, Hinda

    AU - Smith, Craig

    AU - Turbitt, Erin

    AU - Gustin, Sonja

    AU - van den Bergen, Jocelyn

    AU - Miles, Denise

    AU - Western, Patrick

    AU - Arboleda, Valerie

    AU - Schumacher, Valerie

    AU - Gordon, Lavinia

    AU - Bell, Katrina

    AU - Bengtsson, Henrik

    AU - Speed, Terence

    AU - Hutson, John

    AU - Warne, Garry L

    AU - Harley, Vincent

    AU - Koopman, Peter

    AU - Vilain, Eric

    AU - Sinclair, Andrew

    PY - 2011

    Y1 - 2011

    N2 - 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.

    AB - 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.

    UR - http://www.ncbi.nlm.nih.gov/pubmed/21408189

    U2 - 10.1371/journal.pone.0017793

    DO - 10.1371/journal.pone.0017793

    M3 - Article

    VL - 6

    JO - PLoS ONE

    JF - PLoS ONE

    SN - 1932-6203

    IS - 3

    M1 - e17793

    ER -