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

in Endocrine Connections
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  • 1 L Hughes, West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, B15 2TG, United Kingdom of Great Britain and Northern Ireland
  • 2 K McKay Bounford, West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, B15 2TG, United Kingdom of Great Britain and Northern Ireland
  • 3 E Webb, Department of Endocrinology and Diabetes, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, B4 6NH, United Kingdom of Great Britain and Northern Ireland
  • 4 P Dasani, West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, B15 2TG, United Kingdom of Great Britain and Northern Ireland
  • 5 S Clokie, West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, B15 2TG, United Kingdom of Great Britain and Northern Ireland
  • 6 H Chandran, Department of Endocrinology and Diabetes, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, B4 6NH, United Kingdom of Great Britain and Northern Ireland
  • 7 L McCarthy, Department of Endocrinology and Diabetes, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, B4 6NH, United Kingdom of Great Britain and Northern Ireland
  • 8 Z Mohamed, Department of Endocrinology and Diabetes, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, B4 6NH, United Kingdom of Great Britain and Northern Ireland
  • 9 J Kirk, Department of Endocrinology and Diabetes, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, B4 6NH, United Kingdom of Great Britain and Northern Ireland
  • 10 N Krone, Department of Endocrinology and Diabetes, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, B4 6NH, United Kingdom of Great Britain and Northern Ireland
  • 11 S Allen, West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, B15 2TG, United Kingdom of Great Britain and Northern Ireland
  • 12 T Cole, West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, B15 2TG, United Kingdom of Great Britain and Northern Ireland

Correspondence: Trevor Cole, Email: Trevor.Cole@bwnft.nhs.uk

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 supports previous studies, that an NGS panel approach is a clinically useful and cost effective frontline test for patients with DSDs.

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