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

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...

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Autores principales: 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., Srinivasan, Shubha, Titmuss, Angela, Verge, Charles F., Mowat, David, Smith, Grahame, Smith, Janine, Ewans, Lisa, Shalhoub, Carolyn, Crock, Patricia, Cowell, Chris, Leong, Gary M., Ono, Makato, Lafferty, Antony R., Huynh, Tony, Visser, Uma, Choong, Catherine S., McKenzie, Fiona, Pachter, Nicholas, Thompson, Elizabeth M., Couper, Jennifer, Baxendale, Anne, Gecz, Jozef, Wheeler, Benjamin J., Jefferies, Craig, MacKenzie, Karen, Hofman, Paul, Carter, Philippa, King, Richard I., Krausz, Csilla, van Ravenswaaij-Arts, Conny M. A., Looijenga, Leendert, Drop, Sten, Riedl, Stefan, Cools, Martine, Dawson, Angelika, Juniarto, Achmad Zulfa, Khadilkar, Vaman, Khadilkar, Anuradha, Bhatia, Vijayalakshmi, Dũng, Vũ Chí, Atta, Irum, Raza, Jamal, thi Diem Chi, Nguyen, Hao, Tran Kiem, Harley, Vincent, Koopman, Peter, Warne, Garry, Faradz, Sultana, Oshlack, Alicia, Ayers, Katie L., Sinclair, Andrew H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126855/
https://www.ncbi.nlm.nih.gov/pubmed/27899157
http://dx.doi.org/10.1186/s13059-016-1105-y
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author 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.
Srinivasan, Shubha
Titmuss, Angela
Verge, Charles F.
Mowat, David
Smith, Grahame
Smith, Janine
Ewans, Lisa
Shalhoub, Carolyn
Crock, Patricia
Cowell, Chris
Leong, Gary M.
Ono, Makato
Lafferty, Antony R.
Huynh, Tony
Visser, Uma
Choong, Catherine S.
McKenzie, Fiona
Pachter, Nicholas
Thompson, Elizabeth M.
Couper, Jennifer
Baxendale, Anne
Gecz, Jozef
Wheeler, Benjamin J.
Jefferies, Craig
MacKenzie, Karen
Hofman, Paul
Carter, Philippa
King, Richard I.
Krausz, Csilla
van Ravenswaaij-Arts, Conny M. A.
Looijenga, Leendert
Drop, Sten
Riedl, Stefan
Cools, Martine
Dawson, Angelika
Juniarto, Achmad Zulfa
Khadilkar, Vaman
Khadilkar, Anuradha
Bhatia, Vijayalakshmi
Dũng, Vũ Chí
Atta, Irum
Raza, Jamal
thi Diem Chi, Nguyen
Hao, Tran Kiem
Harley, Vincent
Koopman, Peter
Warne, Garry
Faradz, Sultana
Oshlack, Alicia
Ayers, Katie L.
Sinclair, Andrew H.
author_facet 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.
Srinivasan, Shubha
Titmuss, Angela
Verge, Charles F.
Mowat, David
Smith, Grahame
Smith, Janine
Ewans, Lisa
Shalhoub, Carolyn
Crock, Patricia
Cowell, Chris
Leong, Gary M.
Ono, Makato
Lafferty, Antony R.
Huynh, Tony
Visser, Uma
Choong, Catherine S.
McKenzie, Fiona
Pachter, Nicholas
Thompson, Elizabeth M.
Couper, Jennifer
Baxendale, Anne
Gecz, Jozef
Wheeler, Benjamin J.
Jefferies, Craig
MacKenzie, Karen
Hofman, Paul
Carter, Philippa
King, Richard I.
Krausz, Csilla
van Ravenswaaij-Arts, Conny M. A.
Looijenga, Leendert
Drop, Sten
Riedl, Stefan
Cools, Martine
Dawson, Angelika
Juniarto, Achmad Zulfa
Khadilkar, Vaman
Khadilkar, Anuradha
Bhatia, Vijayalakshmi
Dũng, Vũ Chí
Atta, Irum
Raza, Jamal
thi Diem Chi, Nguyen
Hao, Tran Kiem
Harley, Vincent
Koopman, Peter
Warne, Garry
Faradz, Sultana
Oshlack, Alicia
Ayers, Katie L.
Sinclair, Andrew H.
author_sort Eggers, Stefanie
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-016-1105-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-51268552016-12-08 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. Srinivasan, Shubha Titmuss, Angela Verge, Charles F. Mowat, David Smith, Grahame Smith, Janine Ewans, Lisa Shalhoub, Carolyn Crock, Patricia Cowell, Chris Leong, Gary M. Ono, Makato Lafferty, Antony R. Huynh, Tony Visser, Uma Choong, Catherine S. McKenzie, Fiona Pachter, Nicholas Thompson, Elizabeth M. Couper, Jennifer Baxendale, Anne Gecz, Jozef Wheeler, Benjamin J. Jefferies, Craig MacKenzie, Karen Hofman, Paul Carter, Philippa King, Richard I. Krausz, Csilla van Ravenswaaij-Arts, Conny M. A. Looijenga, Leendert Drop, Sten Riedl, Stefan Cools, Martine Dawson, Angelika Juniarto, Achmad Zulfa Khadilkar, Vaman Khadilkar, Anuradha Bhatia, Vijayalakshmi Dũng, Vũ Chí Atta, Irum Raza, Jamal thi Diem Chi, Nguyen Hao, Tran Kiem Harley, Vincent Koopman, Peter Warne, Garry Faradz, Sultana Oshlack, Alicia Ayers, Katie L. Sinclair, Andrew H. Genome Biol Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-016-1105-y) contains supplementary material, which is available to authorized users. BioMed Central 2016-11-29 /pmc/articles/PMC5126855/ /pubmed/27899157 http://dx.doi.org/10.1186/s13059-016-1105-y Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
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.
Srinivasan, Shubha
Titmuss, Angela
Verge, Charles F.
Mowat, David
Smith, Grahame
Smith, Janine
Ewans, Lisa
Shalhoub, Carolyn
Crock, Patricia
Cowell, Chris
Leong, Gary M.
Ono, Makato
Lafferty, Antony R.
Huynh, Tony
Visser, Uma
Choong, Catherine S.
McKenzie, Fiona
Pachter, Nicholas
Thompson, Elizabeth M.
Couper, Jennifer
Baxendale, Anne
Gecz, Jozef
Wheeler, Benjamin J.
Jefferies, Craig
MacKenzie, Karen
Hofman, Paul
Carter, Philippa
King, Richard I.
Krausz, Csilla
van Ravenswaaij-Arts, Conny M. A.
Looijenga, Leendert
Drop, Sten
Riedl, Stefan
Cools, Martine
Dawson, Angelika
Juniarto, Achmad Zulfa
Khadilkar, Vaman
Khadilkar, Anuradha
Bhatia, Vijayalakshmi
Dũng, Vũ Chí
Atta, Irum
Raza, Jamal
thi Diem Chi, Nguyen
Hao, Tran Kiem
Harley, Vincent
Koopman, Peter
Warne, Garry
Faradz, Sultana
Oshlack, Alicia
Ayers, Katie L.
Sinclair, Andrew H.
Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort
title Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort
title_full Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort
title_fullStr Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort
title_full_unstemmed Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort
title_short Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort
title_sort disorders of sex development: insights from targeted gene sequencing of a large international patient cohort
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126855/
https://www.ncbi.nlm.nih.gov/pubmed/27899157
http://dx.doi.org/10.1186/s13059-016-1105-y
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