Endocrine Abstracts

Introduction: Idiopathic central hypogonadism (ICH) is a rare and heterogeneous disease due to defects of GnRH secretion or action. ICH could be associated or not with hypo-anosmia respectively identifying the Kallmann’s syndrome (KS) or the normosmic ICH (nICH). Even though 14 disease genes have been identified, in 70% of patients no genetic cause could be identified, suggesting additional regulatory genes and still unknown mechanisms. Thus, with the aim to identify new candidate genes, we decided to use a new and genome-wide approach on a group of ICH patients that resulted negative to the previous genetic analysis.

Methods: A total of 32 DNA samples from KS and nICH patients and their unaffected relatives were analyzed together with 1864 negative controls from the normal population. Samples were genotyped using 660W-Quad BeadChip Illumina (660.000 SNPs and 100.000 CNVs). The data obtained were analysed using statistical and bioinformatics tools.

Results and conclusions: Our results showed a statistically significant difference in the number of deletions between cases and controls which might indicate a genetic predisposition to ICH. The SNPs analysis allowed us to identify some candidate loci and in particular one gene with strong brain expression and two different microRNA clusters, thus indicating a possible involvement of microRNA in the pathogenesis of ICH. Loss of Heterozygoisity region analysis showed an enrichment for some pathways/families of protein, such as FGFR pathway, cadherins, brain-expressed GPCR and proteins involved in axon guidance. Furthermore analyzing the chromosomal position we found that 8 of the identified genes mapped in a cluster on chromosome 10 originated by an event of genetic duplication from the primitive block that contains the GNRH1. This may indicate that even though the GNRH1 function in this locus is lost during evolution, it is possible that this chromosome block has maintained or developed new functions in the control of reproduction.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details unavailable.