The prevalence of gonadotropin-releasing hormone receptor mutations in a large cohort of patients with hypogonadotropic hypogonadism

Abstract

To determine the prevalence of GNRH receptor (GNRHR) gene mutations in a large cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH). Molecular analysis and genotype/phenotype correlations. University molecular reproductive endocrinology laboratory. North American and Turkish patients with IHH. 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. GNRHR mutations were characterized and compared with the phenotype. The prevalence of GNRHR mutations was also determined. 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. 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.