When Genetic Load Does Not Correlate with Phenotypic Spectrum: Lessons from the GnRH Receptor (GNRHR)
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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.
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Not all patients with these mutations showed early pregnancy losses, indicating a non-genetic component, such as alterations in placental function as a potentially contributing factor.
“Not all patients with these mutations showed early pregnancy losses, indicating a non-genetic component, such as alterations in placental function as a potentially contributing factor67,69,70.”
From Conditional loss of ERK1 and ERK2 results in abnormal placentation and delayed parturition in the mouse (2019) · cites this paper as [69]
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- Authors
- Gianetti, E., Hall, J. E., Au, M. G., Kaiser, U. B., Quinton, R., Stewart, J. A., Metzger, D. L., Pitteloud, N., Mericq, V., Merino, P. M., Levitsky, L. L., Izatt, L., Lang-Muritano, M., Fujimoto, V. Y., Dluhy, R. G., Chase, M. L., Crowley, W. F., Plummer, L., & Seminara, S. B.
- Affiliations
- Harvard University (US)
- Newcastle University (GB)
- Centre for Life (GB)
- BC Children's Hospital (CA)
- Centre Hospitalier Universitaire Vaudois (CH)
- Institute of Maternal and Child Research (V.M.), Santiago de Chile 8389100, Chile
- University of Chile (CL)
- Guy's Hospital (GB)
- Harvard Center for Reproductive Sciences and Reproductive Endocrine Unit (E.G., J.E.H., M.G.A., M.L.C., W.F.C., L.P., S.B.S.), Boston, Massachusetts 02114
- University of California, San Francisco (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Seminara, Stephanie B.
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2012-09-01
- Volume
- 97
- Issue
- 9
- Pages
- E1798-E1807
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC3431570
- OpenAlex
- W2138596875
- Cited by
- 53
- References
- 61
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 6 · 2023: 2 · 2022: 2 · 2021: 6 · 2020: 1 · 2019: 6 · 2018: 3 · 2017: 6 · 2016: 7 · 2015: 6 · 2014: 1 · 2013: 3
- FWCI
- 3.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- IRIS (submittedVersion)
- Universidad de Chile (submittedVersion, cc-by-nc-nd)
- SERVAL (Université de Lausanne) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Massachusetts General Hospital
- National Institutes of Health
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD 42708, R01HD15788, R01 HD19938, R01HD015788, R01HD019938, R01HD043341, R01HD042708, K24HD067388, U54 5U54HD028138, U54HD028138)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Keywords
- GnRH receptor, GnRH deficiency, hypogonadotropic hypogonadism, genetic load, monoallelic variants, biallelic variants, loss-of-function mutations, rare variants, clinical phenotype, genotype-phenotype correlation, reproductive phenotypes
- MeSH terms
- Adolescent, Adult, Amenorrhea, DNA, DNA Mutational Analysis, Ethnicity, Female, Humans, Hypogonadism, Hypothalamic Diseases, Gonadotropin-Releasing Hormone, Male, Mutation, Phenotype, Puberty, Delayed, Receptors, LHRH, Genetic Load, Young Adult
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