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

ABSTRACT: 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.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.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.

SUBMITTER: Eggers S

PROVIDER: S-EPMC5126855 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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

Eggers Stefanie S Sadedin Simon S van den Bergen Jocelyn A JA Robevska Gorjana G Ohnesorg Thomas T Hewitt Jacqueline J Lambeth Luke L Bouty Aurore A Knarston Ingrid M IM Tan Tiong Yang TY Cameron Fergus F Werther George G Hutson John J O'Connell Michele M Grover Sonia R SR Heloury Yves Y Zacharin Margaret M Bergman Philip P Kimber Chris C Brown Justin J Webb Nathalie N Hunter Matthew F MF Hunter Matthew F MF Srinivasan Shubha S Titmuss Angela A Verge Charles F CF Mowat David D Smith Grahame G Smith Janine J Ewans Lisa L Shalhoub Carolyn C Crock Patricia P Cowell Chris C Leong Gary M GM Ono Makato M Lafferty Antony R AR Huynh Tony T Visser Uma U Choong Catherine S CS McKenzie Fiona F Pachter Nicholas N Thompson Elizabeth M EM Couper Jennifer J Baxendale Anne A Gecz Jozef J Wheeler Benjamin J BJ Jefferies Craig C MacKenzie Karen K Hofman Paul P Carter Philippa P King Richard I RI Krausz Csilla C van Ravenswaaij-Arts Conny M A CM Looijenga Leendert L Drop Sten S Riedl Stefan S Cools Martine M Dawson Angelika A Juniarto Achmad Zulfa AZ Khadilkar Vaman V Khadilkar Anuradha A Bhatia Vijayalakshmi V Dũng Vũ Chí VC Atta Irum I Raza Jamal J Thi Diem Chi Nguyen N Hao Tran Kiem TK Harley Vincent V Koopman Peter P Warne Garry G Faradz Sultana S Oshlack Alicia A Ayers Katie L KL Sinclair Andrew H AH

Genome biology 20161129 1

<h4>Background</h4>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.<h4>Results</h4>We analyzed DNA from the l ...[more]

PMID: 27899157

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Project description:Disorders of sex development (DSDs) are congenital conditions in which the external appearance of the individual does not coincide with the chromosomal constitution or the gonadal sex. In other words, there is an ambiguous or intermediate condition between the male and female phenotypes of the anatomical sex. These atypical conditions are manifested in several ways, ranging from genital ambiguity to phenotypes that are so attenuated that they can go unnoticed or appear normal. Currently, there is a lack of understanding of the factors responsible for these outcomes; however, they are likely to be conditioned by genetic, hormonal and environmental factors during prenatal and postnatal development. The present study determined the genetic etiology of DSDs in Colombian patients by conventional cytogenetic analysis, FISH and MLPA (for SF1, DAX1, SOX9, SRY and WNT4). A cohort of 43 patients with clinical phenotypes of sex development disorder was used in the present study. Using this multistep experimental approach, a diagnostic percentage of 25.58% was obtained: 17 patients (39.53%) were classified as having gonadal development disorders, the majority of which were ovotesticular disorders with numerical and/or structural alterations of the sex chromosomes, 9 patients (20.93%) were classified as having testicular DSD with a 46,XY karyotype, and 3 patients (6.98%) as having ovarian DSD with a 46,XX karyotype. The remaining 14 patients (32.56%) were classified as 'other' since they could not be grouped into a specific class of gonadal development, corresponding to hypospadias and multiple congenital anomalies. These findings highlight the importance of histological and cytogenetic studies in a gonadal biopsy. In 11/43 cases, the multistep experimental protocol presented in the present study yielded etiological or histological findings that could be used to define the medical management of patients with DSDs. In conclusion, for the etiological diagnosis of DSDs, a broad?spectrum approach that includes endocrinological tests, conventional karyotyping, molecular karyotyping by FISH and, molecular tests is required, in addition to gonadal tissue analyses, to identify genetic alterations.

Dataset Information

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

Publications

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

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