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 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; Vũ Chí Dũng; 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

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, Vũ Chí Dũng, 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

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

248 Citations (Scopus)

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
Pages (from-to)	243
Journal	Genome biology
Volume	17
Issue number	1
DOIs	https://doi.org/10.1186/s13059-016-1105-y
Publication status	Published - 29 Nov 2016
Externally published	Yes

Keywords

Chromosome Aberrations
Cohort Studies
Disorders of Sex Development/diagnosis
Female
Genetic Association Studies
Genetic Predisposition to Disease
Genetic Variation
Gonads/growth & development
High-Throughput Nucleotide Sequencing
Humans
Male
Mutation/genetics
Ovary/growth & development
Pedigree
Phenotype
Testis/growth & development

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10.1186/s13059-016-1105-y

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Eggers, S., Sadedin, S., van den Bergen, J. A., Robevska, G., Ohnesorg, T., Hewitt, J., Lambeth, L., Bouty, A., Knarston, I. M., Tan, T. Y., 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), 243. Article 243. https://doi.org/10.1186/s13059-016-1105-y

@article{7937c12e2a25449d9254266f0d2708ce,

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 = "Chromosome Aberrations, Cohort Studies, Disorders of Sex Development/diagnosis, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Gonads/growth & development, High-Throughput Nucleotide Sequencing, Humans, Male, Mutation/genetics, Ovary/growth & development, Pedigree, Phenotype, Testis/growth & development",

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 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 Dũng, {Vũ Ch{\'i}} and Irum Atta and Jamal Raza and {Thi Diem Chi}, Nguyen and Hao, {Tran Kiem} and Vincent Harley and Peter Koopman and Garry Warne and Sultana Faradz and Alicia Oshlack and Ayers, {Katie L} and Sinclair, {Andrew H}",

note = "Publisher Copyright: {\textcopyright} 2016 The Author(s).",

year = "2016",

month = nov,

day = "29",

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

language = "English",

volume = "17",

pages = "243",

journal = "Genome biology",

issn = "1474-7596",

publisher = "BioMed Central Ltd.",

number = "1",

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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, 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, Dũng, VC, Atta, I, Raza, J, Thi Diem Chi, N, Hao, TK, 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, pp. 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 - 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 - 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 - Dũng, Vũ Chí

AU - Atta, Irum

AU - Raza, Jamal

AU - Thi Diem Chi, Nguyen

AU - Hao, Tran Kiem

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 - Chromosome Aberrations

KW - Cohort Studies

KW - Disorders of Sex Development/diagnosis

KW - Female

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Gonads/growth & development

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Male

KW - Mutation/genetics

KW - Ovary/growth & development

KW - Pedigree

KW - Phenotype

KW - Testis/growth & development

UR - http://www.scopus.com/inward/record.url?scp=84999143754&partnerID=8YFLogxK

U2 - 10.1186/s13059-016-1105-y

DO - 10.1186/s13059-016-1105-y

M3 - Article

C2 - 27899157

SN - 1474-7596

VL - 17

SP - 243

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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