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
SN - 1932-6203
VL - 6
JO - PLoS ONE
JF - PLoS ONE
IS - 3
M1 - e17793
ER -