Rapid Molecular Genetic Diagnosis with Next-Generation Sequencing in 46,XY Disorders of Sex Development Cases: Efficiency and Cost Assessment

Abstract

Background/Aim: The aim of this study was to use targeted next-generation sequencing (TNGS) including all known genes associated with 46,XY disorders of sex development (DSD) for a fast molecular genetic diagnosis. Methods: Twenty pediatric patients were recruited, and 56 genes related to 46,XY DSD were sequenced using TNGS. The time elapsed between initial appointment and final diagnosis as well as the mean expenditure was determined. Results: A total of 9 (45%) mutations in 4 different genes were identified. Mutations in the HSD17B3 gene were observed in 6 (30%) patients. A heterozygous mutation in WT1 gene and a hemizygous mutation in SRY gene were detected in patients with gonadal dysgenesis. One patient had a homozygous mutation in LHCGR gene. Prior to the molecular diagnosis, the mean number of clinical visits, time elapsed until diagnosis, and expenditure were 27.4 ± 14.6 visits, 5.9 ± 4.1 years per patient, and USD 2,142 ± 1,038, respectively. With TNGS, time elapsed until diagnosis was significantly reduced (3 days), and expenditure per patient was only one third of the conventional approach (USD 761). Conclusions: TNGS is an efficient, rapid, and cost-effective technique for mutation detection in 46,XY DSD.

A novel HSD17B3 gene mutation in a 46,XY female‐phenotype newborn identified by whole‐exome sequencing

“…As in many cases, the endocrine evaluation of patients with 46,XY DSD does not lead to a precise diagnosis, the molecular genetic approach of screening candidate genes is commonly used. However, use of WES has recently become more efficient and less costly in cases where the molecular diagnosis can be challenging, and it is becoming the preferred approach . Knowing the precise molecular genetics is very important not only for an accurate diagnosis and for genetic consultation, but also for the decision regarding gender assignment.…”

NovelNR5A1mutations found in Chinese patients with 46,XYdisorders of sex development

“…Therefore, it is often difficult to precisely determine the underlying cause of 46, XY DSD. Gene sequencing is a useful technique for the precise etiological diagnosis of DSD …”

“…Gene sequencing is a useful technique for the precise etiological diagnosis of DSD. 2,13,14 In this study, we report seven cases of 46, XY DSD caused by NR5A1 mutations and analyze the functional characteristics of novel mutations. 15 Each patient gave their informed written consent for the study, and the study protocol was reviewed and approved by the Peking Union Medical College Hospital ethics committee.…”

Disorders of testicular development in persons with 46, XY-gonadal dysgenesis

“…46,XY ПРС, зумовлене мутацією в гені WT1. WT1 ген (Willms tumor gene) локалізований на хромосомі 11р13 і експресується на ранніх стадіях формування проміжної мезодерми ще до розвитку урогенітальної системи та кодує транскрипційний чинник, що бере участь в розвитку нирок і гонад ембріона [8,[57][58]. Гермінальні гетерозиготні мутації WT1 гену спричиняють дефекти розвитку сечостатевої системи, які в частині випадків супроводжуються виникненням в дитячому віці нефробластоми (пухлини Вільмса).…”