Molecular genetic diagnostics of hypogonadotropic hypogonadism: from panel design towards result interpretation in clinical practice

Abstract

Congenital hypogonadotropic hypogonadism (CHH) is a clinically and genetically heterogeneous congenital disease. Symptoms cover a wide spectrum from mild forms to complex phenotypes due to gonadotropin-releasing hormone (GnRH) deficiency. To date, more than 40 genes have been identified as pathogenic cause of CHH. These genes could be grouped into two major categories: genes controlling development and GnRH neuron migration and genes being responsible for neuroendocrine regulation and GnRH neuron function. High-throughput, next-generation sequencing (NGS) allows to analyze numerous gene sequences at the same time. Nowadays, whole exome or whole genome datasets could be investigated in clinical genetic diagnostics due to their favorable cost-benefit. The increasing genetic data generated by NGS reveal novel candidate genes and gene variants with unknown significance (VUSs). To provide clinically valuable genetic results, complex clinical and bioinformatics work are needed. The multifaceted genetics of CHH, the variable mode of inheritance, the incomplete penetrance, variable expressivity and oligogenic characteristics further complicate the interpretation of the genetic variants detected. The objective of this work, apart from reviewing the currently known genes associated with CHH, was to summarize the advantages and disadvantages of the NGS-based platforms and through the authors' own practice to guide through the whole workflow starting from gene panel design, performance analysis and result interpretation. Based on our results, a genetic diagnosis was clearly identified in 21% of cases tested (8/38). Congenital hypogonadotropic hypogonadism (CHH) Congenital hypogonadotropic hypogonadism (CHH) as a clinically heterogeneous entity Congenital hypogonadotropic hypogonadism (CHH) is a genetic condition characterized by incomplete or absent puberty and infertility due to central (tertiary or hypothalamic) hypogonadism caused by gonadotropic hormonereleasing hormone (GnRH) deficiency. Three clinical forms are distinguished by the European consensus: (1) GnRH deficiency with defective sense of smell (Kallmann syndrome, KS), (2) isolated GnRH deficiency (normosmic CHH) and the third form when KS/CHH is part of a complex genetic syndrome (Boehm et al. 2015). CHH has an incidence of 1:125,000 in female and 1:30,000 in males indicating the male predominance (Stamou and Georgopoulos 2018). CHH has a heterogeneous clinical appearance, and lately the constitutional delay of growth and puberty (CDGP), the adultonset hypogonadotropic hypogonadism and the hypothalamic amenorrhea are also considered as a milder end of the Electronic supplementary material The online version of this article (

Genetics of Azoospermia

“…All the etiological categories of azoospermia include monogenic causes. Some of them are routinely tested in specific pathological conditions, such as CHH and CBAVD [7,8]. The discovery of monogenic defects of quantitative alterations of spermatogenesis due to primary testicular failure is increasing constantly, but their screening has not been introduced into the diagnostic workup of NOA men, so far.…”

“…This review is ai at providing an overview on genetic factors involved in azoospermia. [7,8]; ** 47,XXY Klinefelter syndrome, 46,XX male syndrome, Yq'-'; *** See articles [9][10][11]. [7,8]; ** 47,XXY Klinefelter syndrome, 46,XX male syndrome, Yq'-'; *** See articles [9][10][11].…”

Disease gene discovery in male infertility: past, present and future

“…In addition, NGS has also been instrumental in the study of congenital isolated hypogonadotropic hypogonadism, characterised by incomplete or absent puberty and infertility. A large number of pathogenic mutations have been identified in genes and genetic loci that result in neurodevelopmental defects of gonadotropic hormone-releasing hormone (GnRH) neuron migration or disrupt neuroendocrine GnRH secretion and action (Cangiano et al 2020;Butz et al 2020).…”

Editorial for the special issue on the molecular genetics of male infertility

“…In over 80% of cHH patients, spermatogenesis can be induced by hormonal treatment with the consequent induction of natural pregnancy and potential transmission of the trait. Two articles are dedicated to the genetic dissection of cHH and provide an excellent overview on the complexity and the many peculiarities of this rare disease (Cangiano et al 2021;Butz et al 2021). For instance, cHH only in part follows Mendelian laws of segregation and it represents one of the best proven examples of di/oligogenicity.…”

“…This implies that genetic screening for cHH should be based on a NGS gene panel including a large set of candidate genes. Butz et al (2021) provide useful clinical data on panel design and data interpretation through the comparison of different gene panels in terms of their diagnostic yield.…”