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; null Tiong Yang Tan; Fergus Cameron; George Werther; John Hutson; Michele O'Connell; Sonia R. Grover; Yves Heloury; Margaret Zacharin; Philip Bergman; Chris Kimber; Justin Brown; Nathalie Webb; Matthew F. Hunter; Shubha Srinivasan; Angela Titmuss; Charles F. Verge; David Mowat; Grahame Smith; Janine Smith; Lisa Ewans; Carolyn Shalhoub; Patricia Crock; Chris Cowell; Gary M. Leong; Makato Ono; Antony R. Lafferty; Tony Huynh; Uma Visser; Catherine S. Choong; Fiona McKenzie; Nicholas Pachter; Elizabeth M. Thompson; Jennifer Couper; Anne Baxendale; Jozef Gecz; Benjamin J. Wheeler; Craig Jefferies; Karen MacKenzie; Paul Hofman; Philippa Carter; Richard I. King; Csilla Krausz; Conny M. A. van Ravenswaaij-Arts; Leendert Looijenga; Sten Drop; Stefan Riedl; Martine Cools; Angelika Dawson; Achmad Zulfa Juniarto; Vaman Khadilkar; Anuradha Khadilkar; Vijayalakshmi Bhatia; [No Value] Vu Chi Dung; Irum Atta; Jamal Raza; null Nguyen Thi Diem Chi; null Tran Kiem Hao; Vincent Harley; Peter Koopman; Garry Warne; Sultana Faradz; Alicia Oshlack; Katie L. Ayers; Andrew H. Sinclair

doi:10.1186/s13059-016-1105-y

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, Shubha Srinivasan, Angela Titmuss, Charles F. Verge, David Mowat, Grahame Smith, Janine Smith, Lisa Ewans, Carolyn Shalhoub, Patricia Crock, Chris Cowell, Gary M. Leong, Makato Ono, Antony R. Lafferty, Tony Huynh, Uma Visser, Catherine S. Choong, Fiona McKenzie, Nicholas Pachter, Elizabeth M. Thompson, Jennifer Couper, Anne Baxendale, Jozef Gecz, Benjamin J. Wheeler, Craig Jefferies, Karen MacKenzie, Paul Hofman, Philippa Carter, Richard I. King, Csilla Krausz, Conny M. A. van Ravenswaaij-Arts, Leendert Looijenga, Sten Drop, Stefan Riedl, Martine Cools, Angelika Dawson, Achmad Zulfa Juniarto, Vaman Khadilkar, Anuradha Khadilkar, Vijayalakshmi Bhatia, [No Value] Vu Chi Dung, Irum Atta, Jamal Raza, Nguyen Thi Diem Chi, Tran Kiem Hao, Vincent Harley, Peter Koopman, Garry Warne, Sultana Faradz, Alicia Oshlack, Katie L. Ayers, Andrew H. Sinclair^*

^*Corresponding author for this work

Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Research output: Contribution to journal › Article › Academic › peer-review

259 Citations (Scopus)

654 Downloads (Pure)

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 language	English
Article number	243
Number of pages	21
Journal	Genome Biology
Volume	17
Issue number	1
DOIs	https://doi.org/10.1186/s13059-016-1105-y
Publication status	Published - 29-Nov-2016

Keywords

Disorders of sex development
Gonad
Testis
Ovaries
Ovotestes
Massively parallel sequencing
MPS
Cohort
Targeted gene panel
Genetic diagnosis
Variant
Mutation
ANDROGEN-RECEPTOR GENE
GONADOTROPIN-RELEASING-HORMONE
HUMAN TESTIS DETERMINATION
DESERT-HEDGEHOG GENE
GONADAL-DYSGENESIS
REPEAT LENGTH
MUTATIONS
HYPOSPADIAS
IDENTIFICATION
DIAGNOSIS

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Additional file 1: Table S1. of Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort
Eggers, S. (Contributor), Sadedin, S. (Contributor), Bouty, A. (Contributor), Riedl, S. (Contributor), Webb, N. (Contributor), Looijenga, L. (Contributor), Grover, S. R. (Contributor), Bhatia, V. (Contributor), Hao, T. K. (Contributor), Koopman, P. (Contributor), Shalhoub, C. (Contributor), thi Diem Chi, N. (Contributor), Lambeth, L. (Contributor), Thompson, E. M. (Contributor), Faradz, S. (Contributor), Hutson, J. (Contributor), Carter, P. (Contributor), Khadilkar, V. (Contributor), Warne, G. (Contributor), Kimber, C. (Contributor), Srinivasan, S. (Contributor), Dũng, V. C. (Contributor), Harley, V. (Contributor), Cools, M. (Contributor), Hofman, P. (Contributor), Titmuss, A. (Contributor), Ewans, L. (Contributor), Tan, T. Y. (Contributor), Pachter, N. (Contributor), Krausz, C. (Contributor), O'Connell, M. (Contributor), Drop, S. (Contributor), Crock, P. (Contributor), Brown, J. (Contributor), Knarston, I. M. (Contributor), Zacharin, M. (Contributor), Robevska, G. (Contributor), Visser, U. (Contributor), Heloury, Y. (Contributor), Choong, C. S. (Contributor), Verge, C. F. (Contributor), King, R. I. (Contributor), Atta, I. (Contributor), Khadilkar, A. (Contributor), Ohnesorg, T. (Contributor), Dawson, A. (Contributor), Smith, J. (Contributor), Oshlack, A. (Contributor), Couper, J. (Contributor), Cowell, C. (Contributor), Mowat, D. (Contributor), Gecz, J. (Contributor), Smith, G. (Contributor), Raza, J. (Contributor), van Ravenswaaij-Arts, C. M. A. (Contributor), Bergman, P. (Contributor), Huynh, T. (Contributor), Hunter, M. F. (Contributor), Hewitt, J. (Contributor), McKenzie, F. (Contributor), van den Bergen, J. A. (Contributor), Cameron, F. (Contributor), Leong, G. (Contributor), Juniarto, A. Z. (Contributor), Werther, G. (Contributor), Wheeler, B. J. (Contributor), Lafferty, A. R. (Contributor), MacKenzie, K. (Contributor), Ono, M. (Contributor), Jefferies, C. (Contributor), Baxendale, A. (Contributor), Ayers, K. L. (Creator) & Sinclair, A. H. (Creator), University of Groningen, 14-Dec-2016
DOI: 10.6084/m9.figshare.c.3600380_d2.v1, https://doi.org/10.6084%2Fm9.figshare.c.3600380_d2.v1
Dataset
Additional file 1: Table S1. of Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort
Eggers, S. (Creator), Sadedin, S. (Creator), van den Bergen, J. A. (Contributor), Robevska, G. (Creator), Ohnesorg, T. (Creator), Hewitt, J. (Creator), Lambeth, L. (Creator), Bouty, A. (Creator), Knarston, I. M. (Creator), Tan, T. Y. (Contributor), Cameron, F. (Creator), Werther, G. (Creator), Hutson, J. (Creator), O'Connell, M. (Contributor), Grover, S. R. (Creator), Heloury, Y. (Creator), Zacharin, M. (Creator), Bergman, P. (Creator), Kimber, C. (Creator), Brown, J. (Creator), Webb, N. (Creator), Hunter, M. F. (Creator), Srinivasan, S. (Creator), Titmuss, A. (Creator), Verge, C. F. (Creator), Mowat, D. (Creator), Smith, G. (Creator), Smith, J. (Creator), Ewans, L. (Creator), Shalhoub, C. (Creator), Crock, P. (Creator), Cowell, C. (Creator), Leong, G. (Creator), Ono, M. (Contributor), Lafferty, A. R. (Creator), Huynh, T. (Creator), Visser, U. (Creator), Choong, C. S. (Creator), McKenzie, F. (Creator), Pachter, N. (Creator), Thompson, E. M. (Creator), Couper, J. (Creator), Baxendale, A. (Creator), Gecz, J. (Creator), Wheeler, B. J. (Creator), Jefferies, C. (Creator), MacKenzie, K. (Creator), Hofman, P. (Creator), Carter, P. (Creator), King, R. I. (Creator), Krausz, C. (Creator), van Ravenswaaij-Arts, C. M. A. (Contributor), Looijenga, L. (Creator), Drop, S. (Creator), Riedl, S. (Creator), Cools, M. (Creator), Dawson, A. (Creator), Juniarto, A. Z. (Contributor), Khadilkar, V. (Creator), Khadilkar, A. (Creator), Bhatia, V. (Contributor), Dũng, V. C. (Contributor), Atta, I. (Contributor), Raza, J. (Creator), thi Diem Chi, N. (Contributor), Hao, T. K. (Creator), Harley, V. (Creator), Koopman, P. (Creator), Warne, G. (Creator), Faradz, S. (Creator), Oshlack, A. (Creator), Ayers, K. L. (Creator) & Sinclair, A. H. (Creator), figshare, 29-Nov-2016
DOI: 10.6084/m9.figshare.c.3600380_d2
Dataset

Cite this

Eggers, S., Sadedin, S., van den Bergen, J. A., Robevska, G., Ohnesorg, T., Hewitt, J., Lambeth, L., Bouty, A., Knarston, I. M., Tiong Yang Tan, Cameron, F., Werther, G., Hutson, J., O'Connell, M., Grover, S. R., Heloury, Y., Zacharin, M., Bergman, P., Kimber, C., ... Sinclair, A. H. (2016). Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort. Genome Biology, 17(1), Article 243. https://doi.org/10.1186/s13059-016-1105-y

@article{3899b0427883493f9ff4f458464f7eb9,

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.",

keywords = "Disorders of sex development, Gonad, Testis, Ovaries, Ovotestes, Massively parallel sequencing, MPS, Cohort, Targeted gene panel, Genetic diagnosis, Variant, Mutation, ANDROGEN-RECEPTOR GENE, GONADOTROPIN-RELEASING-HORMONE, HUMAN TESTIS DETERMINATION, DESERT-HEDGEHOG GENE, GONADAL-DYSGENESIS, REPEAT LENGTH, MUTATIONS, HYPOSPADIAS, IDENTIFICATION, DIAGNOSIS",

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 {Tiong Yang Tan} 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 Shubha Srinivasan and Angela Titmuss and Verge, {Charles F.} and David Mowat and Grahame Smith and Janine Smith and Lisa Ewans and Carolyn Shalhoub and Patricia Crock and Chris Cowell and Leong, {Gary M.} and Makato Ono and Lafferty, {Antony R.} and Tony Huynh and Uma Visser and Choong, {Catherine S.} and Fiona McKenzie and Nicholas Pachter and Thompson, {Elizabeth M.} and Jennifer Couper and Anne Baxendale and Jozef Gecz and Wheeler, {Benjamin J.} and Craig Jefferies and Karen MacKenzie and Paul Hofman and Philippa Carter and King, {Richard I.} and Csilla Krausz and {van Ravenswaaij-Arts}, {Conny M. A.} and Leendert Looijenga and Sten Drop and Stefan Riedl and Martine Cools and Angelika Dawson and Juniarto, {Achmad Zulfa} and Vaman Khadilkar and Anuradha Khadilkar and Vijayalakshmi Bhatia and {Vu Chi Dung}, {[No Value]} and Irum Atta and Jamal Raza and {Nguyen Thi Diem Chi} and {Tran Kiem Hao} and Vincent Harley and Peter Koopman and Garry Warne and Sultana Faradz and Alicia Oshlack and Ayers, {Katie L.} and Sinclair, {Andrew H.}",

year = "2016",

month = nov,

day = "29",

doi = "10.1186/s13059-016-1105-y",

language = "English",

volume = "17",

journal = "Genome Biology",

issn = "1465-6906",

publisher = "BMC",

number = "1",

}

Eggers, S, Sadedin, S, van den Bergen, JA, Robevska, G, Ohnesorg, T, Hewitt, J, Lambeth, L, Bouty, A, Knarston, IM, Tiong Yang Tan, 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, Srinivasan, S, Titmuss, A, Verge, CF, Mowat, D, Smith, G, Smith, J, Ewans, L, Shalhoub, C, Crock, P, Cowell, C, Leong, GM, Ono, M, Lafferty, AR, Huynh, T, Visser, U, Choong, CS, McKenzie, F, Pachter, N, Thompson, EM, Couper, J, Baxendale, A, Gecz, J, Wheeler, BJ, Jefferies, C, MacKenzie, K, Hofman, P, Carter, P, King, RI, Krausz, C, van Ravenswaaij-Arts, CMA, Looijenga, L, Drop, S, Riedl, S, Cools, M, Dawson, A, Juniarto, AZ, Khadilkar, V, Khadilkar, A, Bhatia, V, Vu Chi Dung, NV, Atta, I, Raza, J, Nguyen Thi Diem Chi, Tran Kiem Hao, Harley, V, Koopman, P, Warne, G, Faradz, S, Oshlack, A, 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

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 - Tiong Yang Tan, null

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 - Srinivasan, Shubha

AU - Titmuss, Angela

AU - Verge, Charles F.

AU - Mowat, David

AU - Smith, Grahame

AU - Smith, Janine

AU - Ewans, Lisa

AU - Shalhoub, Carolyn

AU - Crock, Patricia

AU - Cowell, Chris

AU - Leong, Gary M.

AU - Ono, Makato

AU - Lafferty, Antony R.

AU - Huynh, Tony

AU - Visser, Uma

AU - Choong, Catherine S.

AU - McKenzie, Fiona

AU - Pachter, Nicholas

AU - Thompson, Elizabeth M.

AU - Couper, Jennifer

AU - Baxendale, Anne

AU - Gecz, Jozef

AU - Wheeler, Benjamin J.

AU - Jefferies, Craig

AU - MacKenzie, Karen

AU - Hofman, Paul

AU - Carter, Philippa

AU - King, Richard I.

AU - Krausz, Csilla

AU - van Ravenswaaij-Arts, Conny M. A.

AU - Looijenga, Leendert

AU - Drop, Sten

AU - Riedl, Stefan

AU - Cools, Martine

AU - Dawson, Angelika

AU - Juniarto, Achmad Zulfa

AU - Khadilkar, Vaman

AU - Khadilkar, Anuradha

AU - Bhatia, Vijayalakshmi

AU - Vu Chi Dung, [No Value]

AU - Atta, Irum

AU - Raza, Jamal

AU - Nguyen Thi Diem Chi, null

AU - Tran Kiem Hao, null

AU - Harley, Vincent

AU - Koopman, Peter

AU - Warne, Garry

AU - Faradz, Sultana

AU - Oshlack, Alicia

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 - Disorders of sex development

KW - Gonad

KW - Testis

KW - Ovaries

KW - Ovotestes

KW - Massively parallel sequencing

KW - MPS

KW - Cohort

KW - Targeted gene panel

KW - Genetic diagnosis

KW - Variant

KW - Mutation

KW - ANDROGEN-RECEPTOR GENE

KW - GONADOTROPIN-RELEASING-HORMONE

KW - HUMAN TESTIS DETERMINATION

KW - DESERT-HEDGEHOG GENE

KW - GONADAL-DYSGENESIS

KW - REPEAT LENGTH

KW - MUTATIONS

KW - HYPOSPADIAS

KW - IDENTIFICATION

KW - DIAGNOSIS

U2 - 10.1186/s13059-016-1105-y

DO - 10.1186/s13059-016-1105-y

M3 - Article

C2 - 27899157

SN - 1465-6906

VL - 17

JO - Genome Biology

JF - Genome Biology

IS - 1

M1 - 243

ER -

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

Abstract

Keywords

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Datasets

Additional file 1: Table S1. of Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort

Additional file 1: Table S1. of Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort

Cite this