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.
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Stefan
authors.initials: S
authors.lastname: White
authors.forename: Thomas
authors.initials: T
authors.lastname: Ohnesorg
authors.forename: Amanda
authors.initials: A
authors.lastname: Notini
authors.forename: Kelly
authors.initials: K
authors.lastname: Roeszler
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Hewitt
authors.forename: Hinda
authors.initials: H
authors.lastname: Daggag
authors.forename: Craig
authors.initials: C
authors.lastname: Smith
authors.forename: Erin
authors.initials: E
authors.lastname: Turbitt
authors.forename: Sonja
authors.initials: S
authors.lastname: Gustin
authors.forename: Jocelyn
authors.initials: J
authors.lastname: van den Bergen
authors.forename: Denise
authors.initials: D
authors.lastname: Miles
authors.forename: Patrick
authors.initials: P
authors.lastname: Western
authors.forename: Valerie
authors.initials: V
authors.lastname: Arboleda
authors.forename: Valerie
authors.initials: V
authors.lastname: Schumacher
authors.forename: Lavinia
authors.initials: L
authors.lastname: Gordon
authors.forename: Katrina
authors.initials: K
authors.lastname: Bell
authors.forename: Henrik
authors.initials: H
authors.lastname: Bengtsson
authors.forename: Terry
authors.initials: T
authors.lastname: Speed
authors.forename: John
authors.initials: J
authors.lastname: Hutson
authors.forename: Garry
authors.initials: G
authors.lastname: Warne
authors.forename: Vincent
authors.initials: V
authors.lastname: Harley
authors.forename: Peter
authors.initials: P
authors.lastname: Koopman
authors.forename: Eric
authors.initials: E
authors.lastname: Vilain
authors.forename: Andrew
authors.initials: A
authors.lastname: Sinclair
mesh_terms: D000465:Algorithms; D000818:Animals; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000235:genetics / Q000378:metabolism; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics; D005786:Gene Expression Regulation; D015321:Gene Rearrangement / Q000235:genetics; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics*; D006066:Gonads / Q000196:embryology / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D055758:SOX9 Transcription Factor / Q000235:genetics
chemical_list: D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D050956:HSP40 Heat-Shock Proteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; C517602:Camk1d protein, mouse