ESPE Abstracts

Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by a dysfunction of the GnRH Axis. The clinical variability of the disease is accompanied by genetic heterogeneity. Indeed, more than 40 genes are implicated in the pathogenesis of this condition. The main goal of this present study was to characterize genetic defects in a large cohort of French CHH patients using a targeted NGS panel.

Patients: a cohort of 120 unrelated patients (77 males/43 females) with CHH (24 Kallmann syndrome, 1 Gordon-Holmes syndrome, 1 Woodhouse-Sakati Syndrome, one 4-Syndrome and 93 normosmic CHH) were studied using a panel of 54 genes.

Results: Pathogenic or probably pathogenic variants were identified in 34 (28%) CHH patients, 13 (11%) of these variants are novel. The most affected genes are CHD7, FGFR1, IGSF10, GNRHR, TACR4 and WDR11. Thirty one patients (26%) had rare variants including variants of uncertain significance (VUS) in more than one candidate gene. The CNV analysis identified two duplications in ANOS1 and a large deletion in GNRHR. The achieved diagnostic rate of the NGS panel was comparable to other genetics studies of CHH.

Conclusion: This is one of the largest genetic study in a french cohort of CHH patients that provide new genetics findings of a rare and heterogeneous disease. The use of a targeted NGS panel is an effective tool to diagnosis CHH patients but it must be completed in some cases with exome and whole genome analysis in order to unravel the complexity of this condition and to move a step closer to a personalised medicine.