Medicine:Genetics of GnRH deficiency conditions
To date, at least 25 different genes have been implicated in causing gonadotropin-releasing hormone (GnRH) deficiency conditions such as Kallmann syndrome (KS) or other forms of congenital hypogonadotropic hypogonadism (CHH) through a disruption in the production or activity of GnRH. These genes involved cover all forms of inheritance, and no one gene defect has been shown to be common to all cases, which makes genetic testing and inheritance prediction difficult.[1][2]
The number of genes known to cause cases of KS/CHH is still increasing.[3] In addition, it is thought that some cases of KS/CHH are caused by two separate gene defects occurring at the same time.[4]
Genes
A table of known genes responsible for cases of GnRH deficiency conditions is shown below. Listed are the estimated prevalence of cases caused by the specific gene, additional associated symptoms and the form of inheritance.[4][5] Between 35 and 45% of cases of KS/CHH have an unknown genetic cause.[6]
Prevalence (%) | OMIM | Name | Gene | Locus | Clinical features | Syndromes associated | Inheritance pattern |
---|---|---|---|---|---|---|---|
5,[4] 5-10[7] | Online Mendelian Inheritance in Man (OMIM) 308700 | ANOS1 (KAL1) | ANOS1 | Xp22.3 | Anosmia. Bimanual synkinesis. Renal agenesis. | x-linked | |
10[4][7] | Online Mendelian Inheritance in Man (OMIM) 147950 | KAL2 | FGFR1 | 8p11.23 | Cleft lip and / or cleft palate. Septo-optic dysplasia. Skeletal anomomalies. Bimanual synkinesis. Hand / foot malformations such as ectrodactyly. Combined pituitary hormone deficiency. | Hartsfield syndrome | Autosomal dominant |
6-16,[4] 5-10[7] | Online Mendelian Inheritance in Man (OMIM) 146110 | GNRHR | GNRHR | 4q13.2 | Autosomal recessive | ||
6,[4] 5-10[7] | Online Mendelian Inheritance in Man (OMIM) 612370 | CHD7 | CHD7 | 8q12.2 | Congenital hearing loss. Semicircular canal hypoplasia. | CHARGE syndrome | Autosomal dominant |
3-6,[4] <2[7] | Online Mendelian Inheritance in Man (OMIM) 610628 | KAL4 | PROK2 | 3p13 | Autosomal recessive | ||
3-6,[4] 5[7] | Online Mendelian Inheritance in Man (OMIM) 244200 | KAL3 | PROKR2 | 20p12.3 | Combined pituitary hormone deficiency. | Morning Glory syndrome | Autosomal recessive |
3,[4] 2-5[7] | Online Mendelian Inheritance in Man (OMIM) 615267 | IL17RD | IL17RD | 3p14.3 | Congenital hearing loss. | Autosomal recessive | |
2,[4] 2-5[7] | Online Mendelian Inheritance in Man (OMIM) 611584 | SOX10 | SOX10 | 22q13.1 | Congenital hearing loss. | Waardenburg syndrome | Autosomal dominant |
2,[4] <2[7] | Online Mendelian Inheritance in Man (OMIM) 614842 | KISS1 | KiSS-1 | 1q32.1 | Autosomal recessive | ||
2,[4] <2[7] | Online Mendelian Inheritance in Man (OMIM) 614837 | KISS1R (GPR54) | GPR54 | 19p13.3 | Autosomal recessive | ||
<2[7] | Online Mendelian Inheritance in Man (OMIM) 612702 | FGF8 | FGF8 | 10q24.32 | Cleft lip and / or cleft palate. Skeletal anomomolies. Bimanual synkinesis. Combined pituitary hormone deficiency. | Autosomal dominant | |
<2,[4] 1 report[7] | Online Mendelian Inheritance in Man (OMIM) 615270 | FGF17 | FGF17 | 8p21.3 | Dandy–Walker syndrome | Autosomal dominant | |
<2[4] | Online Mendelian Inheritance in Man (OMIM) 164260 | LEP | LEP | 7q32.1 | Early onset of morbid obesity. | Autosomal recessive | |
<2[4] | Online Mendelian Inheritance in Man (OMIM) 601007 | LEPR | LEPR | 1p31.3 | Early onset of morbid obesity. | Autosomal recessive | |
<2[4] | Online Mendelian Inheritance in Man (OMIM) 162150 | PCSK1 | PCSK1 | 5q15 | Early onset of morbid obesity. | Autosomal recessive | |
Rare,[4] 1 report[7][8] | Online Mendelian Inheritance in Man (OMIM) 616030 | FEZF1 | FEZF1 | 7q31.32 | Autosomal recessive | ||
Rare,[4] 2 reports [7][9][10][11] | Online Mendelian Inheritance in Man (OMIM) 616031 | CCDC141 | CCDC141 | 2q31.2 | Unknown | ||
Rare,[4] <2[7] | Online Mendelian Inheritance in Man (OMIM) 614897 | SEMA3A | SEMA3A | 7q21.11 | Autosomal dominant | ||
1 report[7] | Online Mendelian Inheritance in Man (OMIM) 608166 | SEMA3E | SEMA3E | 7q21.11 | CHARGE syndrome | Autosomal dominant | |
Rare[4] | Online Mendelian Inheritance in Man (OMIM) 607961 | SEMA7A | SEMA7A | 15q24.1 | Autosomal dominant | ||
Rare,[4] <2[7] | Online Mendelian Inheritance in Man (OMIM) 614880 | HS6ST1 | HS6ST1 | 2q14.3 | Cleft lip and / or cleft palate. Skeletal anomalies. | Autosomal dominant | |
Rare,[4] 1 report[7] | Online Mendelian Inheritance in Man (OMIM) 614858 | WDR11 | WDR11 | 10q26.12 | Combined pituitary hormone deficiency. | Autosomal dominant | |
Rare[4] | Online Mendelian Inheritance in Man (OMIM) 614838 | NELF (NSMF) | NELF | 9q34.3 | Autosomal dominant | ||
Rare[4] | Online Mendelian Inheritance in Man (OMIM) 617351 | IGSF10 | IGSF10 | 3q24 | Autosomal dominant | ||
Rare,[4] <2[7] | Online Mendelian Inheritance in Man (OMIM) 614841 | GNRH1 | GNRH1 | 8p21.2 | Autosomal recessive | ||
Rare,[4] <2[7] | Online Mendelian Inheritance in Man (OMIM) 614839 | TAC3 | TAC3 | 12q3 | Autosomal recessive | ||
Rare,[4] 5[7] | Online Mendelian Inheritance in Man (OMIM) 614840 | TACR3 | TACR3 | 4q24 | Autosomal recessive | ||
Rare[4] | Online Mendelian Inheritance in Man (OMIM) 611744 | OTUD4 | OTUD4 | 4q31.21 | Cerebellar ataxia. | Gordon Holmes syndrome | Autosomal recessive |
Rare[4] | Online Mendelian Inheritance in Man (OMIM) 609948 | RNF216 | RNF216 | 7p22.1 | Cerebellar ataxia. | Gordon Holmes syndrome | Autosomal recessive |
Rare[4] | Online Mendelian Inheritance in Man (OMIM) 603197 | PNPLA6 | PNPLA6 | 19p13.2 | Cerebellar ataxia. | Gordon Holmes syndrome | Autosomal recessive |
1 report[7] | Online Mendelian Inheritance in Man (OMIM) 109135 | AXL | AXL | 19q13.2 | Unknown | ||
Rare[4] | Online Mendelian Inheritance in Man (OMIM) 612186 | DMXL2 | DMXL2 | 15q21.2 | Polyendocrine deficiencies and polyneuropathy. | Autosomal recessive | |
Rare[4] | Online Mendelian Inheritance in Man (OMIM) 300473 | NR0B1 (DAX1) | NR0B1 | Xp21.2 | Adrenal hypoplasia. | x-linked | |
1 report[7] | Online Mendelian Inheritance in Man (OMIM) 602748 | DUSP6 | DUSP6 | 12q21.33 | Autosomal dominant | ||
1 report[7] | Online Mendelian Inheritance in Man (OMIM) 614366 | POLR3B | POLR3B | 12q23.3 | Autosomal recessive | ||
1 report[7] | Online Mendelian Inheritance in Man (OMIM) 615266 | SPRY4 | SPRY4 | 5q31.3 | Autosomal dominant | ||
1 report[7] | Online Mendelian Inheritance in Man (OMIM) 615271 | FLRT3 | FLRT3 | 20p12.1 | Autosomal dominant | ||
1 report[7] | Online Mendelian Inheritance in Man (OMIM) 617264 | SRA1 | SRA1 | 19q13.33 | Unknown | ||
Rare[4] | Online Mendelian Inheritance in Man (OMIM) 601802 | HESX1 | HESX1 | 3p14.3 | Septo-optic dysplasia. Combined pituitary hormone deficiency. | Autosomal recessive and dominant |
See also
- Kallmann syndrome
- Hypogonadotropic hypogonadism
- GnRH
- Isolated hypogonadotropic hypogonadism
References
- ↑ Layman L. (2013). "Clinical Testing for Kallmann Syndrome.". J Clin Endocrinol Metab 98 (5): 1860–1862. doi:10.1210/jc.2013-1624. PMID 23650337.
- ↑ "Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes.". Front Endocrinol (Lausanne) 5 (109): 109. 2014. doi:10.3389/fendo.2014.00109. PMID 25071724.
- ↑ "Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory.". Trends Endocrinol. Metab. 22 (7): 249–58. 2011. doi:10.1016/j.tem.2011.03.002. PMID 21511493.
- ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 4.19 4.20 4.21 4.22 4.23 4.24 4.25 4.26 4.27 4.28 4.29 4.30 4.31 4.32 "Molecular and Genetic Aspects of Congenital Isolated Hypogonadotropic Hypogonadism". Endocrinol Metab Clin North Am 46 (2): 283–303. 2017. doi:10.1016/j.ecl.2017.01.010. PMID 28476224.
- ↑ "Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism-pathogenesis, diagnosis and treatment.". Nat Rev Endocrinol 11 (Jul 21): 547–64. 2015. doi:10.1038/nrendo.2015.112. PMID 26194704.
- ↑ "The complex genetic basis of congenital hypogonadotropic hypogonadism". Minerva Endocrinol 41 (2): 223–39. 2016. PMID 26934720.
- ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 7.14 7.15 7.16 7.17 7.18 7.19 7.20 7.21 7.22 7.23 7.24 7.25 7.26 Balasubramanian R, Crowley WF Jr (2017). "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency". SourceGeneReviews. PMID 20301509.
- ↑ Kotan, LD; Hutchins, BI; Ozkan, Y; Demirel, F; Stoner, H; Cheng, PJ; Esen, I; Gurbuz, F et al. (4 September 2014). "Mutations in FEZF1 cause Kallmann syndrome.". American Journal of Human Genetics 95 (3): 326–31. doi:10.1016/j.ajhg.2014.08.006. PMID 25192046.
- ↑ Hutchins, BI; Kotan, LD; Taylor-Burds, C; Ozkan, Y; Cheng, PJ; Gurbuz, F; Tiong, JD; Mengen, E et al. (May 2016). "CCDC141 Mutation Identified in Anosmic Hypogonadotropic Hypogonadism (Kallmann Syndrome) Alters GnRH Neuronal Migration.". Endocrinology 157 (5): 1956–66. doi:10.1210/en.2015-1846. PMID 27014940.
- ↑ Turan, I; Hutchins, BI; Hacihamdioglu, B; Kotan, LD; Gurbuz, F; Ulubay, A; Mengen, E; Yuksel, B et al. (1 June 2017). "CCDC141 Mutations in Idiopathic Hypogonadotropic Hypogonadism.". The Journal of Clinical Endocrinology and Metabolism 102 (6): 1816–1825. doi:10.1210/jc.2016-3391. PMID 28324054.
- ↑ Hou, Q; Wu, J; Zhao, Y; Wang, X; Jiang, F; Chen, DN; Zheng, R; Men, M et al. (September 2020). "Genotypic and phenotypic spectrum of CCDC141 variants in a Chinese cohort with congenital hypogonadotropic hypogonadism.". European Journal of Endocrinology 183 (3): 245–254. doi:10.1530/EJE-19-1018. PMID 32520725.
Original source: https://en.wikipedia.org/wiki/Genetics of GnRH deficiency conditions.
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