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Oligogenic basis of isolated gonadotropin-releasing hormone deficiency
Open accessAbstract
Between the genetic extremes of rare monogenic and common polygenic diseases lie diverse oligogenic disorders involving mutations in more than one locus in each affected individual. Elucidating the principles of oligogenic inheritance and mechanisms of genetic interactions could help unravel the newly appreciated role of rare sequence variants in polygenic disorders. With few exceptions, however, the precise genetic architecture of oligogenic diseases remains unknown. Isolated gonadotropin-releasing hormone (GnRH) deficiency caused by defective secretion or action of hypothalamic GnRH is a rare genetic disease that manifests as sexual immaturity and infertility. Recent reports of patients who harbor pathogenic rare variants in more than one gene have challenged the long-held view that the disorder is strictly monogenic, yet the frequency and extent of oligogenicity in isolated GnRH deficiency have not been investigated. By systematically defining genetic variants in large cohorts of well-phenotyped patients ( n = 397), family members, and unaffected subjects ( n = 179) for the majority of known disease genes, this study suggests a significant role of oligogenicity in this disease. Remarkably, oligogenicity in isolated GnRH deficiency was as frequent as homozygosity/compound heterozygosity at a single locus (2.5%). Among the 22% of patients with detectable rare protein-altering variants, the likelihood of oligogenicity was 11.3%. No oligogenicity was detected among controls ( P < 0.05), even though deleterious variants were present. Viewing isolated GnRH deficiency as an oligogenic condition has implications for understanding the pathogenesis of its reproductive and nonreproductive phenotypes; deciphering the etiology of common GnRH-related disorders; and modeling the genetic architecture of other oligogenic and multifactorial diseases.
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Cites
A method and server for predicting damaging missense mutations.
Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S., & Sunyaev, S. R. (2010) · Nature Methods · doi:10.1038/nmeth0410-248 · Cited by 13,194
The GPR54 Gene as a Regulator of Puberty
Seminara, S. B., Messager, S., Chatzidaki, E. E., Thresher, R. R., Acierno, J. S., Shagoury, J. K., Bo-Abbas, Y., Kuohung, W., Schwinof, K. M., Hendrick, A. G., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa035322 · Cited by 2,557
Self-citationHypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54
de Roux, N., Genin, E., Carel, J.-C., Matsuda, F., Chaussain, J.-L., & Milgrom, E. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1834399100 · Cited by 2,431 · cited 1×
“Others, however, had single-allele variants in either KISS1R (9%) or GNRHR (6%) (Table S2), which are genes traditionally thought to underlie recessive isolated GnRH deficiency (23, 24, 26).”
BackgroundMultiple Rare Alleles Contribute to Low Plasma Levels of HDL Cholesterol
Cohen, J. C., Kiss, R. S., Pertsemlidis, A., Marcel, Y. L., McPherson, R., & Hobbs, H. H. (2004) · Science · doi:10.1126/science.1099870 · Cited by 1,108
Topaloglu, A. K., Reimann, F., Guclu, M., Yalin, A. S., Kotan, L. D., Porter, K. M., Serin, A., Mungan, N. O., Cook, J. R., Ozbek, M. N., et al. (2009) · Nature Genetics · doi:10.1038/ng.306 · Cited by 961
Rare Variants Create Synthetic Genome-Wide Associations
Dickson, S. P., Wang, K., Krantz, I., Hakonarson, H., & Goldstein, D. B. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000294 · Cited by 857
Franco, B., Guioli, S., Pragliola, A., Incerti, B., Bardoni, B., Tonlorenzi, R., Carrozzo, R., Maestrini, E., Pieretti, M., Taillon-Miller, P., et al. (1991) · Nature · doi:10.1038/353529a0 · Cited by 846
de Roux, N., Young, J., Misrahi, M., Genet, R., Chanson, P., Schaison, G., & Milgrom, E. (1997) · New England Journal of Medicine · doi:10.1056/nejm199711273372205 · Cited by 518
Kallmann Syndrome: Mutations in the Genes Encoding Prokineticin-2 and Prokineticin Receptor-2
Dodé, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., et al. (2006) · PLoS Genetics · doi:10.1371/journal.pgen.0020175 · Cited by 457
Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice
Falardeau, J., Chung, W. C. J., Beenken, A., Raivio, T., Plummer, L., Sidis, Y., Jacobson-Dickman, E. E., Eliseenkova, A. V., Ma, J., Dwyer, A., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34538 · Cited by 397
Self-citation
Research works printed but not linked: 47
- 10.1038/nrg1828 · DOI
- 10.1056/NEJMp0806284 · DOI
- 10.1016/j.cell.2010.03.032 · DOI · Paper page
- 10.1038/ng.118 · DOI · Paper page
- 10.1093/hmg/ddh092 · DOI
- 10.1126/science.8202715 · DOI
- 10.1681/ASN.2007020243 · DOI
- 10.1038/nrg910 · DOI · Paper page
- 10.1210/edrv.19.5.0344 · DOI · Paper page
- J Waldstreicher, et al., The genetic and clinical heterogeneity of gonadotropin-releasing hormone deficiency in the human. J Clin Endocrinol Metab 81, 4388–4395 (1996).
- 10.1073/pnas.0708636104 · DOI
- 10.1159/000314193 · DOI
- 10.1210/en.2007-1634 · DOI
- 10.1002/(SICI)1097-0029(19990101)44:1<2::AID-JEMT2>3.0.CO;2-4 · DOI
- 10.1016/0092-8674(91)90193-3 · DOI · Paper page
- 10.1038/ng1122 · DOI · Paper page
- N de Roux, et al., The same molecular defects of the gonadotropin-releasing hormone receptor determine a variable degree of hypogonadism in affected kindred. J Clin Endocrinol Metab 84, 567–572 (1999).
- 10.1210/jc.2002-021981 · DOI
- 10.1073/pnas.0600962103 · DOI · Paper page
- SB Seminara, et al., Successful use of pulsatile gonadotropin-releasing hormone (GnRH) for ovulation induction and pregnancy in a patient with GnRH receptor mutations. J Clin Endocrinol Metab 85, 556–562 (2000).
- 10.1172/JCI29884 · DOI · Paper page
- 10.1210/jc.2007-2654 · DOI · Paper page
- 10.2164/jandrol.108.005314 · DOI
- 10.1073/pnas.0903449106 · DOI
- 10.1210/jc.2009-0179 · DOI
- 10.1038/nprot.2009.86 · DOI · Paper page
- 10.1126/scitranslmed.3000288 · DOI
- 10.1093/molehr/gan027 · DOI
- 10.1111/j.1365-2265.2009.03642.x · DOI
- 10.1093/hmg/ddn318 · DOI · Paper page
- 10.1530/eje.1.02235 · DOI
- N Pitteloud, et al., The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism: Spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor. J Clin Endocrinol Metab 86, 2470–2475 (2001).
- 10.1210/jc.2002-020806 · DOI
- 10.1210/jc.2009-0843 · DOI
- 10.1016/0303-7207(95)03518-C · DOI
- 10.1002/(SICI)1097-0177(199905)215:1<26::AID-DVDY4>3.0.CO;2-D · DOI
- 10.1242/dev.129.19.4613 · DOI
- 10.1101/gad.250703 · DOI
- 10.1210/jc.2009-2320 · DOI · Paper page
- 10.1056/NEJMoa0900136 · DOI · Paper page
- 10.1172/JCI37041 · DOI · Paper page
- 10.1056/NEJMoa066494 · DOI · Paper page
- 10.1288/00005537-198402000-00004 · DOI
- LM Oliveira, et al., The importance of autosomal genes in Kallmann syndrome: Genotype-phenotype correlations and neuroendocrine characteristics. J Clin Endocrinol Metab 86, 1532–1538 (2001).
- 10.1007/s10038-004-0137-4 · DOI
- 10.1002/(SICI)1098-1004(1998)11:1<1::AID-HUMU1>3.0.CO;2-O · DOI
- 10.1093/nar/gkp215 · DOI
Cited by
Boehm, U., Bouloux, P.-M., Dattani, M. T., de Roux, N., Dodé, C., Dunkel, L., Dwyer, A. A., Giacobini, P., Hardelin, J.-P., Juul, A., et al. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.112 · Cited by 874
Self-citationMiraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., et al. (2013) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2013.04.008 · Cited by 267
Self-citationSEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome
Hanchate, N. K., Giacobini, P., Lhuillier, P., Parkash, J., Espy, C., Fouveaut, C., Leroy, C., Baron, S., Campagne, C., Vanacker, C., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002896 · Cited by 217
Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102284108 · Cited by 177
Self-citationApproach to the patient with hypogonadotropic hypogonadism
Silveira, L. F. G., & Latronico, A. C. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-3550 · Cited by 161
Metadata
- Authors
- Sykiotis, G. P., Plummer, L., Hughes, V. A., Au, M., Durrani, S., Nayak-Young, S., Dwyer, A. A., Quinton, R., Hall, J. E., Gusella, J. F., Seminara, S. B., Crowley, W. F., & Pitteloud, N.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2010-08-09
- Volume
- 107
- Issue
- 34
- Pages
- 15140-15144
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2006433593
- Cited by
- 360
- References
- 15
- FWCI
- 28.64
- Type
- journal article
- Language
- en
- Open access
- green
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