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 well-known 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 fine-tuned guidelines to provide a tool for adequate and precise sequence variant classification in non-Mendelian conditions.

Keywords: Kallmann syndrome; hypothalamic-pituitary-gonadal axis; oligogenicity.

Figure 1

Targeted sequencing identifies oligogenic variants in CHH patients. A – Segregation of identified variants within families. Probands/affected individuals are identified by the arrow. Circles denote females; squares denote males. M: mutation; NT: not tested. B – Sequence chromatograms of affected patients. Family 1: SPRY4: c.722C>A and SEMA3A: c. 1303G>A; M2 chromatogram identifies both a rare variant and a common polymorphism rs7804122 (the dotted line arrow). Family 2: SEMA7A: c. 618_619delCC and CHD7: c. 2840G>A. Family 3: SEMA7A: c. 916G>A and SRA1: c. 377G>A. Family 4: CCDC141: c. 2299G>A and POLR3B: c. 1244T>C; 2570+1G>A. Family 5: PROKR2:c. 889G>T, SPRY4:c. 530A>G, and NSMF: c. 1261C>T. The site of mutation is identified by the arrow

Figure 2

Genes linked to oligogenic inheritance in the studied CHH cohort. A – List of genes with genomic coordinates for the GRCh38 reference assembly. B – Gene-gene interaction based on online tool https://genemania.org/. C – Chromosomal localisation of genes of interest based on https://www.ncbi.nlm.nih.gov/genome/tools/gdp