Clinical characteristics and molecular genetic analysis of a cohort with idiopathic congenital hypogonadism

Ayberk Turkyilmaz; Atilla Cayir; Oguzhan Yarali; Erdal Kurnaz; Emine Kartal Baykan; Esra Arslan Ates; Huseyin Demirbilek

doi:10.1515/jpem-2020-0590

Article

Clinical characteristics and molecular genetic analysis of a cohort with idiopathic congenital hypogonadism

Ayberk Turkyilmaz , Atilla Cayir , Oguzhan Yarali , Erdal Kurnaz , Emine Kartal Baykan , Esra Arslan Ates and Huseyin Demirbilek

Published/Copyright: April 6, 2021

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From the journal Journal of Pediatric Endocrinology and Metabolism Volume 34 Issue 6

Abstract

Objectives

Hypogonadism is defined as inadequate sex hormone production due to defects in the hypothalamic-pituitary-gonadal axis. In recent years, rare single gene defects have been identified in both hypergonadotropic hypogonadism (Hh), and hypogonadotropic hypogonadism (HH) cases with no chromosomal anomalies. The aim of the present study is to investigate the underlying molecular genetic etiology and the genotype-phenotype relationship of a series of patients with Hh and HH.

Methods

In total, 27 HH and six Hh cases were evaluated. Clinical and laboratory features are extracted from patients’ hospital files. Whole exome sequencing (WES) analysis was performed.

Results

A total of 27 HH cases (15 female) (mean age: 15.8 ± 2.7 years) and six Hh patients (six females) (mean age: 14.9 ± 1.2 years) were included. In molecular genetic analysis, a pathogenic/likely pathogenic variant was identified in five (two patients from the same family) of 27 HH cases (two novel) and three of the six Hh. In HH group variants (pathogenic, likely pathogenic and variant of uncertain significance) were identified in KISS1R (n=2), PROK2 (n=1), FGFR1 (n=1), HS6ST1 (n=1), GNRH1 (n=1) genes. In the Hh group, splice-site mutations were detected in DCAF17 (n=1) and MCM9 (n=2) genes.

Conclusions

HH and Hh cases are genetically heterogeneous diseases due to oligogenic inheritance, incomplete penetrance, and variable expressivity. We found rare variants in CHH related genes in half of our HH cases, whereas they classified as pathogenic/likely pathogenic according to ACMG criteria in only about 15% of HH cases. Using advanced genetic analysis methods such as whole-genome sequencing and long-read sequencing may increase the mutation detection rate, which should always be associated with and expert genetic counseling to interpret the data.

Keywords: hypergonadotropic hypogonadism; hypogonadotropic hypogonadism; novel variant; whole-exome sequencing

Corresponding author: Atilla Cayir, MD, Clinics of Paediatric Endocrinology, Erzurum Regional Training and Research Hospital, Erzurum, Turkey, Phone: +905331382744, Fax: +904422382389, E-mail: dratillacayir@gmail.com

Acknowledgments

The authors wish to thank the individuals and their families for their participation in this study, as well as the clinicians for providing patient samples and information.

Research funding: None declared.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/jpem-2020-0590).

Received: 2020-10-12

Accepted: 2021-03-19

Published Online: 2021-04-06

Published in Print: 2021-06-25

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Keywords for this article

hypergonadotropic hypogonadism; hypogonadotropic hypogonadism; novel variant; whole-exome sequencing