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. 2012 Sep;97(9):E1798-807.
doi: 10.1210/jc.2012-1264. Epub 2012 Jun 28.

When genetic load does not correlate with phenotypic spectrum: lessons from the GnRH receptor (GNRHR)

Elena Gianetti  1 , Janet E Hall, Margaret G Au, Ursula B Kaiser, Richard Quinton, Jane A Stewart, Daniel L Metzger, Nelly Pitteloud, Veronica Mericq, Paulina M Merino, Lynne L Levitsky, Louise Izatt, Mariarosaria Lang-Muritano, Victor Y Fujimoto, Robert G Dluhy, Matthew L Chase, William F Crowley Jr, Lacey Plummer, Stephanie B Seminara
Affiliations

When genetic load does not correlate with phenotypic spectrum: lessons from the GnRH receptor (GNRHR)

Elena Gianetti et al. J Clin Endocrinol Metab. 2012 Sep.

Abstract

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.

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Figures

Fig. 1.
Fig. 1.
Functional assessment of RSV.
Fig. 2.
Fig. 2.
Phenotype of individuals included in the four groups. White bar, normal allele; black bar, complete loss of function mutation(s); white and black bar, partial loss of function mutation(s).
Fig. 3.
Fig. 3.
Relationship between the phenotype of patients harboring loss-of-function mutations and the number/severity of GnRH mutations.
See this image and copyright information in PMC

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