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

White S, 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 G, Harley V, Koopman P, Vilain E, Sinclair A - PLoS ONE (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.

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.

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CNV analysis of three 46,XY GD cases using the AROMA algorithm.Data are plotted along each chromosome, with each point represents the copy number estimate of an individual probe. The horizontal solid black line denotes the predicted copy number of the genomic region. For each panel coverage of 2 Mb is shown, with numbers on the horizontal axis corresponding to the March 2006 human reference sequence (hg18). A) Duplication of ∼708 kb on the X-chromosome in case 13. B) Deletion of 1.193 Mb on chromosome 17 in case 10. C) Deletion of 35 kb on chromosome 8 in case 14.
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pone-0017793-g001: CNV analysis of three 46,XY GD cases using the AROMA algorithm.Data are plotted along each chromosome, with each point represents the copy number estimate of an individual probe. The horizontal solid black line denotes the predicted copy number of the genomic region. For each panel coverage of 2 Mb is shown, with numbers on the horizontal axis corresponding to the March 2006 human reference sequence (hg18). A) Duplication of ∼708 kb on the X-chromosome in case 13. B) Deletion of 1.193 Mb on chromosome 17 in case 10. C) Deletion of 35 kb on chromosome 8 in case 14.

Mentions: Three cases had rearrangements that affected genes known to play a role in sex determination or gonad development (for all CNVs identified in these cases see table S2). Firstly, a 708 kb duplication on the X chromosome was identified in case 13 (Figure 1a). This 46,XY DSD patient was diagnosed with complete gonadal dysgenesis and no other clinical features were reported. One of the seven genes contained within the duplicated region was DAX1 (NR0B1), which has been previously been shown to be duplicated in 46,XY complete gonadal dysgenesis.


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

White S, 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 G, Harley V, Koopman P, Vilain E, Sinclair A - PLoS ONE (2011)

CNV analysis of three 46,XY GD cases using the AROMA algorithm.Data are plotted along each chromosome, with each point represents the copy number estimate of an individual probe. The horizontal solid black line denotes the predicted copy number of the genomic region. For each panel coverage of 2 Mb is shown, with numbers on the horizontal axis corresponding to the March 2006 human reference sequence (hg18). A) Duplication of ∼708 kb on the X-chromosome in case 13. B) Deletion of 1.193 Mb on chromosome 17 in case 10. C) Deletion of 35 kb on chromosome 8 in case 14.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3049794&req=5

pone-0017793-g001: CNV analysis of three 46,XY GD cases using the AROMA algorithm.Data are plotted along each chromosome, with each point represents the copy number estimate of an individual probe. The horizontal solid black line denotes the predicted copy number of the genomic region. For each panel coverage of 2 Mb is shown, with numbers on the horizontal axis corresponding to the March 2006 human reference sequence (hg18). A) Duplication of ∼708 kb on the X-chromosome in case 13. B) Deletion of 1.193 Mb on chromosome 17 in case 10. C) Deletion of 35 kb on chromosome 8 in case 14.
Mentions: Three cases had rearrangements that affected genes known to play a role in sex determination or gonad development (for all CNVs identified in these cases see table S2). Firstly, a 708 kb duplication on the X chromosome was identified in case 13 (Figure 1a). This 46,XY DSD patient was diagnosed with complete gonadal dysgenesis and no other clinical features were reported. One of the seven genes contained within the duplicated region was DAX1 (NR0B1), which has been previously been shown to be duplicated in 46,XY complete gonadal dysgenesis.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.

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.

Show MeSH
Related in: MedlinePlus