Whole-exome sequencing analysis of idiopathic hypogonadotropic hypogonadism: comparison of varicocele and non-obstructive azoospermia

Abstract Background As a rare disease leading to male infertility, A has strong heterogeneity of clinical phenotype and gene mutation. At present, there is no effective diagnosis and treatment method for this disease, and the research on its pathogenesis is not exhaustive Objectives To explore the possible new pathogenic gene of idiopathic hypogonadotrophic hypogonadism and the pathological mechanism affecting its occurrence. Patients and methods: We performed a whole-exome sequencing on 9 patients with normosmic idiopathic hypogonadotropic hypogonadism (nIHH), 19 varicocele patients with weak sperm, oligospermia or azoospermia and 5 patients with simple nonobstructive azoospermia and carried out comparative analysis, channel analysis, etc. Results After preliminary sequencing screening, 309–431 genes harbouring variants, including SNPs and indels, were predicted to be harmful per single patient in each group. In genetic variations of nIHH patients’ analysis, variants were detected in 10 loci and nine genes in nine patients. And in co-analysis of the three patient groups, nine nIHH patients, 19 VC patients, and five SN patients shared 116 variants, with 28 variant-harbouring genes detected in five or more patients. After that, we found that many genes crossed among groups and selected the highest number of 17 genes for analysis. Conclusion We found that the NEFH, CCDC177 and PCLO genes and the Gene Ontology pathways GO:0051301: cell division and GO:0090066: regulation of anatomical structure size may be key factors in the pathogenic mechanism of IHH. Our results suggest the pathogenic mechanism of IHH is not limited to the central nervous system effects of GnRH but may involve other heterogeneous pathogenic genetic variants that affect peripheral organs.