TY - JOUR

T1 - The genetic diagnosis of rare endocrine disorders of sex development and maturation

T2 - a survey among Endo-ERN centres

AU - Persani, Luca

AU - Cools, Martine

AU - Ioakim, Stamatina

AU - Ahmed, S. Faisal

AU - Andonova, Silvia

AU - Avbelj-Stefanija, Magdalena

AU - Baronio, Federico

AU - Bouligand, Jerome

AU - Bruggenwirth, Hennie T.

AU - Davies, Justin H.

AU - De Baere, Elfride

AU - Dzivite-Krisane, Iveta

AU - Fernandez-Alvarez, Paula

AU - Gheldof, Alexander

AU - Giavoli, Claudia

AU - Gravholt, Claus H.

AU - Hiort, Olaf

AU - Holterhus, Paul-Martin

AU - Juul, Anders

AU - Krausz, Csilla

AU - Lagerstedt-Robinson, Kristina

AU - McGowan, Ruth

AU - Neumann, Uta

AU - Novelli, Antonio

AU - Peyrassol, Xavier

AU - Phylactou, Leonidas A.

AU - Rohayem, Julia

AU - Touraine, Philippe

AU - Westra, Dineke

AU - Vezzoli, Valeria

AU - Rossetti, Raffaella

N1 - Publisher Copyright: © 2022 The authors Published by Bioscientifica Ltd.

PY - 2022

Y1 - 2022

N2 - 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 conditions, 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. The response rate was 49% with a total of 26 HCPs from 13 countries. All HCPs, except 1, performed NGS investigations for SDM disorders on 6720 patients, 3764 (56%) with differences of sex development (DSD), including 811 unexplained primary ovarian insufficiency, 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 the extraction of a virtual panel in the 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.

AB - 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 conditions, 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. The response rate was 49% with a total of 26 HCPs from 13 countries. All HCPs, except 1, performed NGS investigations for SDM disorders on 6720 patients, 3764 (56%) with differences of sex development (DSD), including 811 unexplained primary ovarian insufficiency, 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 the extraction of a virtual panel in the 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.

KW - congenital hypogonadotropic hypogonadism

KW - disorders of sex development

KW - next-generation sequencing

KW - primary ovarian insufficiency

KW - rare diseases or syndromes

U2 - 10.1530/EC-22-0367

DO - 10.1530/EC-22-0367

M3 - Journal article

C2 - 36228316

AN - SCOPUS:85143912696

VL - 11

JO - Endocrine Connections

JF - Endocrine Connections

SN - 2049-3614

IS - 12

M1 - e220367

ER -