The genetic diagnosis of rare endocrine disorders of sex development and maturation: a survey among Endo-ERN centres

Abstract

Differences of sex development and maturation (SDM) represent a heterogeneous puzzle of rare conditions with a large genetic component whose management and treatment could be improved by an accurate classification of underlying molecular condition and Next Generation Sequencing (NGS) should represent the most appropriate approach. Therefore, we conducted a survey dedicated to the use and potential outcomes of NGS for SDM disorders diagnosis among the 53 health care providers (HCP) of the European Reference Network for rare endocrine conditions (ENDO-ERN). Response rate was 49% with a total of 26 HCPs from 13 countries. All HCPs, except one, performed NGS investigations for SDM disorders on 6720 patients, 3764 (56%) with Differences of Sex Development (DSD), including 811 unexplained Primary Ovarian Insufficiency (POI), and 2956 (44%) with Congenital Hypogonadotropic Hypogonadism (CHH). The approaches varied from targeted analysis of custom gene panels (range: 11-490 genes) in 81.5% of cases or Whole Exome Sequencing with extraction of a virtual panel in remaining cases. These analyses were performed for diagnostic purposes in 21 HCPs, supported by the National Health Systems in 16 cases. The likelihood of finding a variant ranged between 7 and 60%, mainly depending upon the number of analysed genes or criteria used for reporting, most HCPs also reporting variants of uncertain significance. These data illustrate the status of genetic diagnosis of DSD and CHH across Europe. In most countries these analyses are performed for diagnostic purposes, yielding highly variable results, thus suggesting the need for harmonization and general improvements of NGS approaches.

Panel testing for the molecular genetic diagnosis of congenital hypogonadotropic hypogonadism – a clinical perspective

“…Further, it would expand the potential to identify di-or oligogenic carriage in an individual who might otherwise be diagnosed with a monogenic inheritance. A very recent survey of the current practice in European centres shows that while the majority of centres are using candidate panel analysis for CHH diagnostics, a small number of centres already offer whole exome sequencing analysis at initial testing, with a clinical report given on a virtual candidate gene panel [75]. The informative mutation yields are, as expected, much higher with such an approach.…”

Epigenetic control of SOX9 gene by the histone acetyltransferase P300 in human Sertoli cells

“…The latter considers sequence and copy number variants without any transcriptomic or epigenetic research [ 4 ]. The likelihood of finding a specific genetic diagnosis with the current approach has ranged between 7 and 60 % [ 40 , 41 ]. Our results highlight the importance of considering mechanisms beyond specific DNA changes involved in expression anomalies of SOX9 , such as epigenetic markers, which are not currently included in the diagnostic evaluation.…”