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Coding sequence analysis of GNRHR and GPR54 in patients with congenital and adult-onset forms of hypogonadotropic hypogonadism

Reproductive Endocrine Unit, Massachusetts General Hospital BHX 504, Fruit Street, Boston, Massachusetts 02114, USA, ¹ Department of Endocrinology, GATA Haydarpasa Training Hospital, Kadlkoy, Istanbul, Turkey, ² Department of Pediatrics, University of Montreal, Montreal, Canada and ³ Department of Endocrinology, Royal Free Hospital, London, UK

(Correspondence should be addressed to S B Seminara; Email: sseminara{at}partners.org)

Abstract

Objective: To determine the frequency of rare nucleotide variants in GNRHR and GPR54 in a large cohort of probands (n = 166) with normosmic idiopathic hypogonadotropic hypogonadism (nIHH), characterized by mode of inheritance, testicular volume, and presence or absence of endogenous LH pulsations.

Methods: Whenever possible, probands answered detailed questionnaires, underwent full physical exams, and underwent q 10-min frequent blood sampling for LH. Exons segments for GNRHR and GPR54 were screened for mutations. Nucleotide changes were identified as rare variants if they occurred at less than 1% frequency in an ethnically matched control population.

Results: Sixty-two percent of male probands were classified as sporadic, meaning that no other family members had delayed puberty or nIHH. In contrast, 61% of female probands were from familial pedigrees, with either autosomal dominant or autosomal recessive inheritance. Patients displayed a broad spectrum of disease severity based on testicular size and endogenous LH pulsations. Twenty-four rare variants were identified in GNRHR (within 15 probands) and seven rare variants in GPR54 (within five probands).

Conclusions: Rare variants in GNRHR are more common than GPR54 in a nIHH population.

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