Disorders of sex development: Insights from targeted gene sequencing of a large international patient cohort

Stefanie Eggers, Simon Sadedin, Jocelyn A. van den Bergen, Gorjana Robevska, Thomas Ohnesorg, Jacqueline Hewitt, Luke Lambeth, Aurore Bouty, Ingrid M. Knarston, Tiong Yang Tan, Fergus Cameron, George Werther, John Hutson, Michele O'Connell, Sonia R. Grover, Yves Heloury, Margaret Zacharin, Philip Bergman, Chris Kimber, Justin BrownNathalie Webb, Matthew F. Hunter, Antony R. Lafferty, Vincent Harley, Peter Koopman, Katie L. Ayers, Andrew H. Sinclair

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Abstract

Background: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Article number243
Number of pages21
JournalGenome Biology
Volume17
Issue number1
DOIs
Publication statusPublished - 29 Nov 2016

Keywords

  • Cohort
  • Disorders of sex development
  • Genetic diagnosis
  • Gonad
  • Massively parallel sequencing
  • MPS
  • Mutation
  • Ovaries
  • Ovotestes
  • Targeted gene panel
  • Testis
  • Variant

Cite this

Eggers, S., Sadedin, S., van den Bergen, J. A., Robevska, G., Ohnesorg, T., Hewitt, J., ... Sinclair, A. H. (2016). Disorders of sex development: Insights from targeted gene sequencing of a large international patient cohort. Genome Biology, 17(1), [243]. https://doi.org/10.1186/s13059-016-1105-y
Eggers, Stefanie ; Sadedin, Simon ; van den Bergen, Jocelyn A. ; Robevska, Gorjana ; Ohnesorg, Thomas ; Hewitt, Jacqueline ; Lambeth, Luke ; Bouty, Aurore ; Knarston, Ingrid M. ; Tan, Tiong Yang ; Cameron, Fergus ; Werther, George ; Hutson, John ; O'Connell, Michele ; Grover, Sonia R. ; Heloury, Yves ; Zacharin, Margaret ; Bergman, Philip ; Kimber, Chris ; Brown, Justin ; Webb, Nathalie ; Hunter, Matthew F. ; Lafferty, Antony R. ; Harley, Vincent ; Koopman, Peter ; Ayers, Katie L. ; Sinclair, Andrew H. / Disorders of sex development : Insights from targeted gene sequencing of a large international patient cohort. In: Genome Biology. 2016 ; Vol. 17, No. 1.
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title = "Disorders of sex development: Insights from targeted gene sequencing of a large international patient cohort",
abstract = "Background: 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. Results: 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. Conclusions: 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.",
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author = "Stefanie Eggers and Simon Sadedin and {van den Bergen}, {Jocelyn A.} and Gorjana Robevska and Thomas Ohnesorg and Jacqueline Hewitt and Luke Lambeth and Aurore Bouty and Knarston, {Ingrid M.} and Tan, {Tiong Yang} and Fergus Cameron and George Werther and John Hutson and Michele O'Connell and Grover, {Sonia R.} and Yves Heloury and Margaret Zacharin and Philip Bergman and Chris Kimber and Justin Brown and Nathalie Webb and Hunter, {Matthew F.} and Lafferty, {Antony R.} and Vincent Harley and Peter Koopman and Ayers, {Katie L.} and Sinclair, {Andrew H.}",
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Eggers, S, Sadedin, S, van den Bergen, JA, Robevska, G, Ohnesorg, T, Hewitt, J, Lambeth, L, Bouty, A, Knarston, IM, Tan, TY, Cameron, F, Werther, G, Hutson, J, O'Connell, M, Grover, SR, Heloury, Y, Zacharin, M, Bergman, P, Kimber, C, Brown, J, Webb, N, Hunter, MF, Lafferty, AR, Harley, V, Koopman, P, Ayers, KL & Sinclair, AH 2016, 'Disorders of sex development: Insights from targeted gene sequencing of a large international patient cohort', Genome Biology, vol. 17, no. 1, 243. https://doi.org/10.1186/s13059-016-1105-y

Disorders of sex development : Insights from targeted gene sequencing of a large international patient cohort. / Eggers, Stefanie; Sadedin, Simon; van den Bergen, Jocelyn A.; Robevska, Gorjana; Ohnesorg, Thomas; Hewitt, Jacqueline; Lambeth, Luke; Bouty, Aurore; Knarston, Ingrid M.; Tan, Tiong Yang; Cameron, Fergus; Werther, George; Hutson, John; O'Connell, Michele; Grover, Sonia R.; Heloury, Yves; Zacharin, Margaret; Bergman, Philip; Kimber, Chris; Brown, Justin; Webb, Nathalie; Hunter, Matthew F.; Lafferty, Antony R.; Harley, Vincent; Koopman, Peter; Ayers, Katie L.; Sinclair, Andrew H.

In: Genome Biology, Vol. 17, No. 1, 243, 29.11.2016.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Disorders of sex development

T2 - Insights from targeted gene sequencing of a large international patient cohort

AU - Eggers, Stefanie

AU - Sadedin, Simon

AU - van den Bergen, Jocelyn A.

AU - Robevska, Gorjana

AU - Ohnesorg, Thomas

AU - Hewitt, Jacqueline

AU - Lambeth, Luke

AU - Bouty, Aurore

AU - Knarston, Ingrid M.

AU - Tan, Tiong Yang

AU - Cameron, Fergus

AU - Werther, George

AU - Hutson, John

AU - O'Connell, Michele

AU - Grover, Sonia R.

AU - Heloury, Yves

AU - Zacharin, Margaret

AU - Bergman, Philip

AU - Kimber, Chris

AU - Brown, Justin

AU - Webb, Nathalie

AU - Hunter, Matthew F.

AU - Lafferty, Antony R.

AU - Harley, Vincent

AU - Koopman, Peter

AU - Ayers, Katie L.

AU - Sinclair, Andrew H.

PY - 2016/11/29

Y1 - 2016/11/29

N2 - Background: 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. Results: 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. Conclusions: 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.

AB - Background: 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. Results: 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. Conclusions: 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.

KW - Cohort

KW - Disorders of sex development

KW - Genetic diagnosis

KW - Gonad

KW - Massively parallel sequencing

KW - MPS

KW - Mutation

KW - Ovaries

KW - Ovotestes

KW - Targeted gene panel

KW - Testis

KW - Variant

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U2 - 10.1186/s13059-016-1105-y

DO - 10.1186/s13059-016-1105-y

M3 - Article

AN - SCOPUS:84999143754

VL - 17

JO - Genome Biology

JF - Genome Biology

SN - 1474-760X

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ER -