The Prevalence of Gonadotropin-releasing Hormone Receptor Mutations in a Large Cohort of Patients with Hypogonadotropic Hypogonadism

Objective: To determine the prevalence of GNRH receptor (GNRHR) gene mutations in a large cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH).

Design: Molecular analysis and genotype/phenotype correlations.

Setting: University molecular reproductive endocrinology laboratory.

Patient(s): North American and Turkish patients with IHH.

Intervention(s): DNA from 185 IHH patients were subjected to denaturing gradient gel electrophoresis for exons and splice junctions of the GNRHR gene. Variant fragments were sequenced.

Main Outcome Measure(s): GNRHR mutations were characterized and compared with the phenotype. The prevalence of GNRHR mutations was also determined.

Result(s): Three of 185 (1.6%; confidence interval [CI] 0.3%-4.7%) total IHH patients demonstrated compound heterozygous GNRHR mutations. All three were identified from a cohort of 85 normosmic patients (3.5%, CI 0.73%-7.5%), and none were demonstrated in hyposmic or anosmic IHH patients. GNRHR mutations were identified in 1 of 15 (6.7%; CI 0.2%-32.0%) families with at least two affected siblings, and in 2 of 18 (11.1%; CI 1.4%-34.7%) normosmic females. None were found in presumably autosomal dominant families.

Conclusion(s): GNRHR mutations account for approximately 3.5% of all normosmic and 7%-11% of presumed autosomal recessive IHH, suggesting that additional genes play an important role in normal puberty. We believe this to be the largest GNRHR gene mutation analysis performed to date in a population of IHH patients.