Arid
DOI10.1186/s13059-016-1105-y
Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort
Eggers, Stefanie1,4; Sadedin, Simon1,2; van den Bergen, Jocelyn A.1; Robevska, Gorjana1; Ohnesorg, Thomas1; Hewitt, Jacqueline1,5,9; Lambeth, Luke1; Bouty, Aurore1,3; Knarston, Ingrid M.1,2; Tiong Yang Tan1,2,3,4; Cameron, Fergus1,3; Werther, George1,3; Hutson, John1,2; O’Connell, Michele1,3; Grover, Sonia R.1,2,3; Heloury, Yves1,3; Zacharin, Margaret1,3; Bergman, Philip6,7; Kimber, Chris8; Brown, Justin6,10; Webb, Nathalie9; Hunter, Matthew F.10,11; Srinivasan, Shubha12; Titmuss, Angela12; Verge, Charles F.13,14; Mowat, David15; Smith, Grahame16,17,18; Smith, Janine19; Ewans, Lisa20,21; Shalhoub, Carolyn15; Crock, Patricia23; Cowell, Chris12; Leong, Gary M.26; Ono, Makato24; Lafferty, Antony R.27,28; Huynh, Tony26; Visser, Uma13; Choong, Catherine S.29,30; McKenzie, Fiona30,31; Pachter, Nicholas30,31; Thompson, Elizabeth M.32,33; Couper, Jennifer34,35; Baxendale, Anne32; Gecz, Jozef33,35,36; Wheeler, Benjamin J.37; Jefferies, Craig38; MacKenzie, Karen39; Hofman, Paul40; Carter, Philippa41; King, Richard I.42; Krausz, Csilla43; van Ravenswaaij-Arts, Conny M. A.44; Looijenga, Leendert45; Drop, Sten46; Riedl, Stefan47,48; Cools, Martine49; Dawson, Angelika50,51,52; Juniarto, Achmad Zulfa53; Khadilkar, Vaman54,55; Khadilkar, Anuradha54,55; Bhatia, Vijayalakshmi56; Vu Chi Dung57; Atta, Irum58; Raza, Jamal58; Nguyen Thi Diem Chi59; Tran Kiem Hao59; Harley, Vincent22; Koopman, Peter25; Warne, Garry2,3; Faradz, Sultana53; Oshlack, Alicia1,5; Ayers, Katie L.1,2; Sinclair, Andrew H.1,2
通讯作者Sinclair, Andrew H.
来源期刊GENOME BIOLOGY
ISSN1474-760X
出版年2016
卷号17
英文摘要

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.


英文关键词Disorders of sex development Gonad Testis Ovaries Ovotestes Massively parallel sequencing MPS Cohort Targeted gene panel Genetic diagnosis Variant Mutation
类型Article
语种英语
国家Australia ; Japan ; New Zealand ; Italy ; Netherlands ; Austria ; Belgium ; Canada ; Indonesia ; India ; Vietnam ; Pakistan
收录类别SCI-E
WOS记录号WOS:000389376400001
WOS关键词ANDROGEN-RECEPTOR GENE ; GONADOTROPIN-RELEASING-HORMONE ; HUMAN TESTIS DETERMINATION ; DESERT-HEDGEHOG GENE ; GONADAL-DYSGENESIS ; REPEAT LENGTH ; MUTATIONS ; HYPOSPADIAS ; IDENTIFICATION ; DIAGNOSIS
WOS类目Biotechnology & Applied Microbiology ; Genetics & Heredity
WOS研究方向Biotechnology & Applied Microbiology ; Genetics & Heredity
来源机构University of Western Australia
资源类型期刊论文
条目标识符http://119.78.100.177/qdio/handle/2XILL650/193146
作者单位1.Murdoch Childrens Res Inst, Melbourne, Vic, Australia;
2.Univ Melbourne, Dept Paediat, Melbourne, Vic, Australia;
3.Royal Childrens Hosp Melbourne, Melbourne, Vic, Australia;
4.Victorian Clin Genet Serv, Melbourne, Vic, Australia;
5.Univ Melbourne, Sch Biosci, Melbourne, Vic, Australia;
6.Monash Childrens Hosp, Dept Paediat Endocrinol & Diabet, Clayton, Vic, Australia;
7.Monash Med Ctr, Clayton, Vic, Australia;
8.Monash Childrens Hosp, Clayton, Vic, Australia;
9.Monash Childrens Hosp, Dept Paediat Urol, Clayton, Vic, Australia;
10.Monash Univ, Dept Paediat, Clayton, Vic, Australia;
11.Monash Hlth, Monash Genet, Clayton, Vic, Australia;
12.Childrens Hosp Westmead, Inst Endocrinol & Diabet, Westmead, NSW, Australia;
13.Sydney Childrens Hosp, Randwick, NSW, Australia;
14.UNSW, Sch Womens & Childrens Hlth, Sydney, NSW, Australia;
15.Sydney Childrens Hosp, Dept Med Genet, Randwick, NSW, Australia;
16.Childrens Hosp Westmead, Urol Program, Westmead, NSW, Australia;
17.Childrens Hosp Westmead, Clin Program, Westmead, NSW, Australia;
18.Univ Sydney, Westmead, NSW, Australia;
19.Childrens Hosp Westmead, Dept Clin Genet, Westmead, NSW, Australia;
20.Royal Prince Alfred Hosp, Dept Med Genom, Camperdown, NSW, Australia;
21.Univ Sydney, Sydney Med Sch, Genet Med, Sydney, NSW, Australia;
22.Hudson Inst Med Res, Clayton, Vic, Australia;
23.John Hunter Childrens Hosp, New Lambton Hts, NSW, Australia;
24.Tokyo Bay Med Ctr, Dept Paediat, Chiba, Japan;
25.Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia;
26.Lady Cilento Childrens Hosp, Dept Paediat Endocrinol & Diabet, Brisbane, Qld, Australia;
27.Centenary Hosp Women & Children, Canberra, ACT, Australia;
28.ANU Med Sch, Canberra, ACT, Australia;
29.Princess Margaret Hosp, Dept Endocrinol & Diabet, Subiaco, WA, Australia;
30.Univ Western Australia, Sch Paediat & Child Hlth, Crawley, WA, Australia;
31.King Edward Mem Hosp, Genet Serv Western Australia, Subiaco, WA, Australia;
32.Womens & Childrens Hosp, SA Pathol, SA Clin Genet Serv, Adelaide, SA, Australia;
33.Univ Adelaide, Sch Med, North Terrace, Adelaide, SA, Australia;
34.Univ Adelaide, Womens & Childrens Hosp, Adelaide, SA, Australia;
35.Univ Adelaide, Robinson Res Inst, Adelaide, SA, Australia;
36.South Australian Hlth & Med Res Inst, Adelaide, SA, Australia;
37.Univ Otago, Dept Womens & Childrens Hlth, Dunedin, New Zealand;
38.Auckland Dist Hlth Board, Diabet & Endocrinol, Auckland, New Zealand;
39.Christchurch Hosp, Christchurch, New Zealand;
40.Univ Auckland, Liggins Inst, Auckland, New Zealand;
41.Starship Paediat Diabet & Endocrinol, Auckland, New Zealand;
42.Canterbury Hlth Labs, Canterbury, New Zealand;
43.Univ Florence, Dept Expt & Clin Biomed Sci Mario Serio, Florence, Italy;
44.Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands;
45.Erasmus Univ, Med Ctr, Josephine Nefkens Inst, Dept Pathol, Rotterdam, Netherlands;
46.Erasmus Univ, Med Ctr, Sophia Childrens Hosp, Dept Paediat,Div Endocrinol, Rotterdam, Netherlands;
47.St Anna Childrens Hosp, Vienna, Austria;
48.Med Univ Vienna, Dept Paediat, Vienna, Austria;
49.Ghent Univ Hosp, Dept Paediat Endocrinol, Ghent, Belgium;
50.Diagnost Serv Manitoba, Genom Lab, Winnipeg, MB, Canada;
51.WRHA, Genet & Metab Program, Winnipeg, MB, Canada;
52.Univ Manitoba, Dept Biochem & Med Genet & Paediat & Child Hlth, Winnipeg, MB, Canada;
53.FMDU, Ctr Biomed Res, Div Human Genet, Semarang, Indonesia;
54.Hirabai Cowasji Jehangir Med Res Inst, Growth & Pediat Endocrine Clin, Pune, Maharashtra, India;
55.Hirabai Cowasji Jehangir Med Res Inst, Pune, Maharashtra, India;
56.Sanjay Gandhi PGI, Dept Endocrinol, Lucknow, Uttar Pradesh, India;
57.Natl Childrens Hosp, Dept Endocrinol Metab & Genet, Hanoi, Vietnam;
58.Natl Inst Child Hlth, Karachi, Pakistan;
59.Hue Cent Hosp, Paediat Ctr, Hue City, Vietnam
推荐引用方式
GB/T 7714
Eggers, Stefanie,Sadedin, Simon,van den Bergen, Jocelyn A.,et al. Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort[J]. University of Western Australia,2016,17.
APA Eggers, Stefanie.,Sadedin, Simon.,van den Bergen, Jocelyn A..,Robevska, Gorjana.,Ohnesorg, Thomas.,...&Sinclair, Andrew H..(2016).Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort.GENOME BIOLOGY,17.
MLA Eggers, Stefanie,et al."Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort".GENOME BIOLOGY 17(2016).
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