title: Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort.
abstract: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously.
  
  
  
  We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46,XY DSD and 48 with 46,XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46,XY DSD. In patients with 46,XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management.
  
  
  
  Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes.
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia.|Victorian Clinical Genetic Services, Melbourne, VIC, Australia.
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authors.lastname: Eggers
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
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authors.lastname: Sadedin
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia.
authors.forename: Jocelyn A
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authors.lastname: van den Bergen
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia.
authors.forename: Gorjana
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authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia.
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authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia.|University of Melbourne, School of Bioscience, Melbourne, VIC, Australia.|Department Of Paediatric Urology, Monash Children's Hospital, Clayton, VIC, Australia.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Hewitt
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia.
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authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia.|The Royal Children's Hospital Melbourne, Melbourne, VIC, Australia.
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authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
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authors.initials: IM
authors.lastname: Knarston
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.|The Royal Children's Hospital Melbourne, Melbourne, VIC, Australia.|Victorian Clinical Genetic Services, Melbourne, VIC, Australia.
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authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia.|The Royal Children's Hospital Melbourne, Melbourne, VIC, Australia.
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authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia.|The Royal Children's Hospital Melbourne, Melbourne, VIC, Australia.
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authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
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authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia.|The Royal Children's Hospital Melbourne, Melbourne, VIC, Australia.
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authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.|The Royal Children's Hospital Melbourne, Melbourne, VIC, Australia.
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authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia.|The Royal Children's Hospital Melbourne, Melbourne, VIC, Australia.
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authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia.|The Royal Children's Hospital Melbourne, Melbourne, VIC, Australia.
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authors.affiliation: Monash Children's Hospital, Clayton, VIC, Australia.
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authors.affiliation: Department Of Paediatric Urology, Monash Children's Hospital, Clayton, VIC, Australia.
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authors.affiliation: Department of Paediatrics, Monash University, Clayton, VIC, Australia.|Monash Genetics, Monash Health, Clayton, VIC, Australia.
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authors.affiliation: The Children's Hospital at Westmead, Institute of Endocrinology and Diabetes, Westmead, NSW, Australia.
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authors.affiliation: Department of Medical Genetics, Sydney Children's Hospital, Randwick, NSW, Australia.
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authors.affiliation: Department of Medical Genetics, Sydney Children's Hospital, Randwick, NSW, Australia.
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authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia.|University of Melbourne, School of Bioscience, Melbourne, VIC, Australia.
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authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
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authors.initials: KL
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authors.affiliation: Murdoch Childrens Research Institute, Melbourne, VIC, Australia. andrew.sinclair@mcri.edu.au.|Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia. andrew.sinclair@mcri.edu.au.
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mesh_terms: D002869:Chromosome Aberrations; D015331:Cohort Studies; D012734:Disorders of Sex Development / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006066:Gonads / Q000254:growth & development / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D010053:Ovary / Q000254:growth & development / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D013737:Testis / Q000254:growth & development / Q000473:pathology
keywords: Cohort; Disorders of sex development; Genetic diagnosis; Gonad; MPS; Massively parallel sequencing; Mutation; Ovaries; Ovotestes; Targeted gene panel; Testis; Variant