ESPE Abstracts (2019) 92 P2-250

High Prevalence GnRH Receptor Mutations in Russian Patients with Idiopathic Hypogonadotropic Hypogonadism

Elena Frolova1, Nina Makretskaya2, Natalya Kalinchenko2, Anna Kolodkina2, Natalya Zubkova2, Vasiliy Petrov2, Evgeniy Vasilyev2, Anatoly Tiulpakov2

1National Medical Research Center of Children's Health, Moscow, Russian Federation. 2Endocrinology Research Centre, Moscow, Russian Federation

Background: GNRHR gene mutations are responsible for development to normosmic idiopathic hypogonadotropic hypogonadism (iHH) and known to be the most frequent cause of this condition. Nevertherless, the reported frequency of GNRHR mutations in iHH patients estimated to be as low as 3-6%.

Objective: To evaluate the frequency of GNRHR gene defects in a heterogeneous group of Russian patients with iHH and described the phenotype of patients with identified defects.

Methods: 144 patients with iHH (119 boys, 25 girls) were included in the study, 51 of them had olfactory impairment. 'Hypogonadotropic hypogonadism panel' genes were sequenced using a custom Ion Ampliseq gene panel and PGM semiconductor sequencer (Ion Torrent). The panel included genes: CHD7, DNMT3L, DUSP6, FGF17, FGF8, FGFR1, FLRT3, GNRH1, GNRHR, HS6ST1, IL17RD, INSL3, KAL1, KISS1, KISS1R, LHB, NELF, POLR3B, PROKR2, RBM28, SEMA3A, SPRY4, TACR3, WDR11, GREAT, TAC3, KAL4, NR0B1, POLR3A, MKRN3. Interpretation of the sequencing results and assessment of the pathogenicity of sequence variants were performed according to the ACMG guidelines (2015).

Results: 4 sequence variants in GNRHR were detected in 15 patients (11%), 4 girls and 11 boys. The most frequent mutations in our group were p.R139H (n=13), p.M1T (n=6) and p.R262Q (n=3). Mutations in GNRHR were detected as part of digenic defects in 2 cases: with a hemizygous mutation p.E156Gfs5X in KAL1; with heterozygous mutation p.V248M in FGFR1.

One patient was hyposmic with a digenic defect in GNRHR and KAL1.

Conclusions: A high percent (10%) iHH due to mutations in GNRHR gene was detected in the heterogeneous group of patients (normosmic iHH and KS). 13 cases of hypogonadism were completely explained by the identified changes in GnRH receptor gene. In a patient with the digenic defect in GNRHR and KAL1 genes, hypogonadism can be due to changes in each of these genes. The defects in GNRHR and FGFR1 genes probably potentiate each other

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