New findings in oligogenic inheritance of congenital hypogonadotropic hypogonadism

Abstract

Introduction: Congenital hypogonadotropic hypogonadism results from a dysfunction of the hypothalamic-pituitary-gonadal axis, which is essential for the development and function of the reproductive system. It may be associated with anosmia, referred to as Kallmann syndrome, or a normal sense of smell. Numerous studies have proven that hypogonadotropic hypogonadism is not simply a monogenic Mendelian disease, but that more than one gene may be involved in its pathogenesis in a single patient. The oligogenic complex architecture underlying the disease is still largely unknown. Material and methods: Targeted next-generation sequencing (NGS) was used to screen for DNA variants in a cohort of 47 patients with congenital hypogonadotropic hypogonadism. The NGS panel consists of over 50 wellknown and candidate genes, associated with hypogonadotropic state. Results: Here we report the identification of new oligogenic variants in SPRY4/SEMA3A, SRA1/SEMA7A, CHD7/SEMA7A, CCDC141/POLR3B/POLR3B, and PROKR2/SPRY4/NSMF. These genes are known to contribute to the phenotype of hypogonadotropic hypogonadism, yet our results point to potential new "partners" underlying digenic and trigenic patterns. Conclusions: The finding supports the importance of oligogenic inheritance and demonstrates the complexity of genetic architecture in hypogonadotropic hypogonadism. It also underlines the necessity for developing finetuned guidelines to provide a tool for adequate and precise sequence variant classification in non-Mendelian conditions.

Variety of genetic defects in GnRH and hypothalamic–pituitary signaling and development in normosmic patients with IHH

“…Therefore, their functional impact is difficult to estimate, while the action of extra-genetic factors cannot be excluded. The phenotypic complexity is further evidenced by new reports of oligogenicity and a growing role of causatives of accumulated milder variants in a single patient ( 19 , 28 , 39 ). A thorough bioinformatic analysis of data obtained in NGS and dedicated genetic panels (considering the clinical picture) is necessary.…”

Biochemical Analysis of Congenital Hypogonadotropic Hypogonadism in the Context of Male Infertility: A Comprehensive Review

“…Identified genetic factors contributing to CHH include: KISS1 and KISS1R (GPR54): Mutations in the KISS1 gene, which encodes kisspeptin, and its receptor, KISS1R (also known as GPR54), can lead to CHH by disrupting the regulation of GnRH secretion. This disruption results in an inadequate release of GnRH, which is critical for the initiation and maintenance of puberty (17).…”

Whole exome data prioritization unveils the hidden weight of Mendelian causes of male infertility. A report from the first Italian cohort

“…Given that both genes are players of the HH pathway, we propose a digenic inheritance to be further explored in this context [11]. Furthermore, HH genes have been already associated to digenic inheritance [52]. Variant in DHX37 is probably neutral because mutations in DHX37 have been associated to high serum levels of FSH and LH (MIM: 273250), although our patient (OSR8) had low levels of both gonadotropins (i.e., LH = 1.3 mUI/mL; FSH = 2.4 mUI/mL).…”