Next Generation Sequencing for Disorders of Sex Development

2014 ◽  
pp. 53-62 ◽  
Author(s):  
Edward S. Tobias ◽  
Ken McElreavey
Keyword(s):  
Next Generation Sequencing ◽  
Disorders Of Sex Development ◽  
Next Generation ◽  
Sex Development ◽  
Generation Sequencing

scholarly journals Next generation sequencing (NGS) to improve the diagnosis and management of patients with disorders of sex development (DSD)

2019 ◽  
Vol 8 (2) ◽  
pp. 100-110 ◽  
Author(s):  
L A Hughes ◽  
K McKay-Bounford ◽  
E A Webb ◽  
P Dasani ◽  
S Clokie ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Patient Management ◽  
Diagnostic Yield ◽  
Management Strategies ◽  
Genetic Diagnosis ◽  
Disorders Of Sex Development ◽  
Next Generation ◽  
Sex Development ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Disorders of sex development (DSDs) are a diverse group of conditions where the chromosomal, gonadal or anatomical sex can be atypical. The highly heterogeneous nature of this group of conditions often makes determining a genetic diagnosis challenging. Prior to next generation sequencing (NGS) technologies, genetic diagnostic tests were only available for a few of the many DSD-associated genes, which consequently had to be tested sequentially. Genetic testing is key in establishing the diagnosis, allowing for personalised management of these patients. Pinpointing the molecular cause of a patient’s DSD can significantly impact patient management by informing future development needs, altering management strategies and identifying correct inheritance pattern when counselling family members. We have developed a 30-gene NGS panel, designed to be used as a frontline test for all suspected cases of DSD (both 46,XX and 46,XY cases). We have confirmed a diagnosis in 25 of the 80 patients tested to date. Confirmed diagnoses were linked to mutations in AMH, AMHR2, AR, HSD17B3, HSD3B2, MAMLD1, NR5A1, SRD5A2 and WT1 which have resulted in changes to patient management. The minimum diagnostic yield for patients with 46,XY DSD is 25/73. In 34/80 patients, only benign or likely benign variants were identified, and in 21/80 patients only variants of uncertain significance (VOUS) were identified, resulting in a diagnosis not being confirmed in these individuals. Our data support previous studies that an NGS panel approach is a clinically useful and cost-effective frontline test for patients with DSDs.

scholarly journals CBX2-dependent transcriptional landscape: implications for human sex development and its defects

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Patrick Sproll ◽  
Wassim Eid ◽  
Anna Biason-Lauber
Keyword(s):  
Next Generation Sequencing ◽  
Rna Sequencing ◽  
Current Knowledge ◽  
Next Generation ◽  
Steroidogenic Factor 1 ◽  
Sex Development ◽  
New Genes ◽  
Differences Of Sex Development ◽  
Generation Sequencing ◽  
Transcriptional Landscape

Abstract Sex development, a complex and indispensable process in all vertebrates, has still not been completely elucidated, although new genes involved in sex development are constantly being discovered and characterized. Chromobox Homolog 2 (CBX2) is one of these new additions and has been identified through a 46,XY girl with double heterozygous variants on CBX2.1, causing Differences of Sex Development (DSD). The mutated CBX2.1 failed to adequately regulate downstream targets important for sex development in humans, specifically steroidogenic factor 1 (NR5A1/SF1). To better place CBX2.1 in the human sex developmental cascade, we performed siRNA and CBX2.1 overexpression experiments and created a complete CRISPR/Cas9-CBX2 knockout in Sertoli-like cells. Furthermore, we deployed Next Generation Sequencing techniques, RNA-Sequencing and DamID-Sequencing, to identify new potential CBX2.1 downstream genes. The combination of these two next generation techniques enabled us to identify genes that are both bound and regulated by CBX2.1. This allowed us not only to expand our current knowledge about the influence of CBX2.1 in human sex development, but also to advance our insight in the mechanisms governing one of the most important decisions during embryonal development, the commitment to either female or male gonads.

scholarly journals Next-Generation Sequencing Reveals Novel Genetic Variants (SRY, DMRT1, NR5A1, DHH, DHX37) in Adults With 46,XY DSD

2019 ◽  
Vol 3 (12) ◽  
pp. 2341-2360 ◽  
Author(s):  
Federica Buonocore ◽  
Oliver Clifford-Mobley ◽  
Tom F J King ◽  
Niccolò Striglioni ◽  
Elim Man ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Gonadal Dysgenesis ◽  
Androgen Insensitivity Syndrome ◽  
Study Cohort ◽  
Next Generation ◽  
Specific Diagnosis ◽  
Androgen Insensitivity ◽  
Sex Development ◽  
Deficiency Type ◽  
Generation Sequencing

Abstract Context The genetic basis of human sex development is slowly being elucidated, and >40 different genetic causes of differences (or disorders) of sex development (DSDs) have now been reported. However, reaching a specific diagnosis using traditional approaches can be difficult, especially in adults where limited biochemical data may be available. Objective We used a targeted next-generation sequencing approach to analyze known and candidate genes for DSDs in individuals with no specific molecular diagnosis. Participants and Design We studied 52 adult 46,XY women attending a single-center adult service, who were part of a larger cohort of 400 individuals. Classic conditions such as17β-hydroxysteroid dehydrogenase deficiency type 3, 5α-reductase deficiency type 2, and androgen insensitivity syndrome were excluded. The study cohort had broad working diagnoses of complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25), a group that included partial gonadal dysgenesis and those with a broad “partial androgen insensitivity syndrome” label. Targeted sequencing of 180 genes was undertaken. Results Overall, a likely genetic cause was found in 16 of 52 (30.8%) individuals (22.2% CGD, 40.0% pvDSD). Pathogenic variants were found in sex-determining region Y (SRY; n = 3), doublesex and mab-3–related transcription factor 1 (DMRT1; n = 1), NR5A1/steroidogenic factor-1 (SF-1) (n = 1), and desert hedgehog (DHH; n = 1) in the CGD group, and in NR5A1 (n = 5), DHH (n = 1), and DEAH-box helicase 37 (DHX37; n = 4) in the pvDSD group. Conclusions Reaching a specific diagnosis can have clinical implications and provides insight into the role of these proteins in sex development. Next-generation sequencing approaches are invaluable, especially in adult populations or where diagnostic biochemistry is not possible.

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