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When Genetic Load Does Not Correlate with Phenotypic Spectrum: Lessons from the GnRH Receptor (GNRHR)

Lookup NU author(s): Dr Richard Quinton, Dr Jane Stewart


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Context: A broad spectrum of GnRH-deficient phenotypes has been identified in individuals with both mono-and biallelic GNRHR mutations. Objective: The objective of the study was to determine the correlation between the severity of the reproductive phenotype(s) and the number and functional severity of rare sequence variants in GNRHR. Subjects: Eight hundred sixty-three probands with different forms of GnRH deficiency, 46 family members and 422 controls were screened for GNRHR mutations. The 70 subjects (32 patients and 38 family members) harboring mutations were divided into four groups (G1-G4) based on the functional severity of the mutations (complete or partial loss of function) and the number of affected alleles (monoallelic or biallelic) with mutations, and these classes were mapped on their clinical phenotypes. Results: The prevalence of heterozygous rare sequence variants in GNRHR was significantly higher in probands vs. controls (P < 0.01). Among the G1-G3 groups (homozygous subjects with successively decreasing severity and number of mutations), the hypogonadotropic phenotype related to their genetic load. In contrast, subjects in G4, with only monoallelic mutations, demonstrated a greater diversity of clinical phenotypes. Conclusions: In patients with GnRH deficiency and biallelic mutations in GNRHR, genetic burden defined by severity and dose is associated with clinical phenotype. In contrast, for patients with monoallelic GNRHR mutations this correlation does not hold. Taken together, these data indicate that as-yet-unidentified genetic and/or environmental factors may combine with singly mutated GNRHR alleles to produce reproductive phenotypes. (J Clin Endocrinol Metab 97: E1798-E1807, 2012)

Publication metadata

Author(s): Gianetti E, Hall JE, Au MG, Kaiser UB, Quinton R, Stewart JA, Metzger DL, Pitteloud N, Mericq V, Merino PM, Levitsky LL, Izatt L, Lang-Muritano M, Fujimoto VY, Dluhy RG, Chase ML, Crowley WF, Plummer L, Seminara SB

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Endocrinology and Metabolism

Year: 2012

Volume: 97

Issue: 9

Pages: E1798-E1807

Print publication date: 28/06/2012

ISSN (print): 0021-972X

ISSN (electronic): 1945-7197

Publisher: The Endocrine Society


DOI: 10.1210/jc.2012-1264


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Funder referenceFunder name
U54 5U54HD028138Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health, Specialized Cooperative Centers Program in Reproduction and Infertility Research