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

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.

Digenic Congenital Hypogonadotropic Hypogonadism Due to Heterozygous GNRH1 p.R31C and AMHR2 p.G445_L453del Variants

“…Case reports of mutations in GNRH1 in CHH are rare. There have been reported 13 biallelic cases in 10 families, all with severe reproductive phenotype, including cryptorchidism in three out of six males, but not with an associated nonreproductive phenotype [ 9 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. There are five digenic case reports with GNRH1 mutations in combination with FGFR1 (4 cases) or DAX1 (1 case) [ 9 , 32 , 33 ].…”

<b><i>GNRH1</i></b> Variants in Congenital Hypogonadotropic Hypogonadism: Single-Center Experience and Systematic Literature Review

“…After exclusions (as detailed in Fig. 1), 12 studies were included in the final analysis yielding a cohort of 19 probands (4,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). For the reported probands and their affected family members, demographic and phenotypic details, genetic variants, and treatment outcomes were recorded.…”

“…To date, only a few cases of CHH with GNRH1 variants have been reported worldwide. Most of them harbor biallelic variants with an autosomal recessive mode of inheritance [4,[9][10][11][12][13][14]. Monoallelic variants with or without oligogenicity have also been reported [9,[15][16][17][18][19].…”

Molecular functions of MCM8 and MCM9 and their associated pathologies

“…As with other MCM components, MCM8 and MCM9 have been implicated in initiation of DNA replication, 7 , 8 , 9 , 10 as well as in meiosis, 9 , 11 , 12 , 13 , 14 homologous recombination (HR) 15 , 16 , 17 , 18 , 19 , 20 , 21 and mismatch repair (MMR). 20 , 22 , 23 Correspondingly, the number of studies describing the possible involvement of MCM8 and MCM9 in pathologies has increased enormously, with disrupting variants of the MCM8/MCM9 genes that follow an autosomal recessive inheritance pattern linked to infertility in both males and females, 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 as well as recently highlighted roles for the MCM8/MCM9 genes in polyposis, 23 , 37 , 38 (early onset) colorectal cancer (OMIM 114500 ) 23 , 37 , 38 and multiple other cancer types. 23 , 34 , 37 , 38 …”