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

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) techn...

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Autores principales: Hughes, L A, McKay-Bounford, K, Webb, E A, Dasani, P, Clokie, S, Chandran, H, McCarthy, L, Mohamed, Z, Kirk, J M W, Krone, N P, Allen, S, Cole, T R P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Bioscientifica Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373624/
https://www.ncbi.nlm.nih.gov/pubmed/30668521
http://dx.doi.org/10.1530/EC-18-0376
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author Hughes, L A
McKay-Bounford, K
Webb, E A
Dasani, P
Clokie, S
Chandran, H
McCarthy, L
Mohamed, Z
Kirk, J M W
Krone, N P
Allen, S
Cole, T R P
author_facet Hughes, L A
McKay-Bounford, K
Webb, E A
Dasani, P
Clokie, S
Chandran, H
McCarthy, L
Mohamed, Z
Kirk, J M W
Krone, N P
Allen, S
Cole, T R P
author_sort Hughes, L A
collection PubMed
description 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.
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spelling pubmed-63736242019-02-20 Next generation sequencing (NGS) to improve the diagnosis and management of patients with disorders of sex development (DSD) Hughes, L A McKay-Bounford, K Webb, E A Dasani, P Clokie, S Chandran, H McCarthy, L Mohamed, Z Kirk, J M W Krone, N P Allen, S Cole, T R P Endocr Connect Research 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. Bioscientifica Ltd 2019-01-16 /pmc/articles/PMC6373624/ /pubmed/30668521 http://dx.doi.org/10.1530/EC-18-0376 Text en © 2019 The authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Research
Hughes, L A
McKay-Bounford, K
Webb, E A
Dasani, P
Clokie, S
Chandran, H
McCarthy, L
Mohamed, Z
Kirk, J M W
Krone, N P
Allen, S
Cole, T R P
Next generation sequencing (NGS) to improve the diagnosis and management of patients with disorders of sex development (DSD)
title Next generation sequencing (NGS) to improve the diagnosis and management of patients with disorders of sex development (DSD)
title_full Next generation sequencing (NGS) to improve the diagnosis and management of patients with disorders of sex development (DSD)
title_fullStr Next generation sequencing (NGS) to improve the diagnosis and management of patients with disorders of sex development (DSD)
title_full_unstemmed Next generation sequencing (NGS) to improve the diagnosis and management of patients with disorders of sex development (DSD)
title_short Next generation sequencing (NGS) to improve the diagnosis and management of patients with disorders of sex development (DSD)
title_sort next generation sequencing (ngs) to improve the diagnosis and management of patients with disorders of sex development (dsd)
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373624/
https://www.ncbi.nlm.nih.gov/pubmed/30668521
http://dx.doi.org/10.1530/EC-18-0376
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