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
[edit]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] | 308700 | ANOS1 (KAL1) | ANOS1 | Xp22.3 | Anosmia. Bimanual synkinesis. Renal agenesis. | x-linked | |
| 10[4][7] | 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] | 146110 | GNRHR | GNRHR | 4q13.2 | Autosomal recessive | ||
| 6,[4] 5-10[7] | 612370 | CHD7 | CHD7 | 8q12.2 | Congenital hearing loss. Semicircular canal hypoplasia. | CHARGE syndrome | Autosomal dominant |
| 3-6,[4] <2[7] | 610628 | KAL4 | PROK2 | 3p13 | Autosomal recessive | ||
| 3-6,[4] 5[7] | 244200 | KAL3 | PROKR2 | 20p12.3 | Combined pituitary hormone deficiency. | Morning Glory syndrome | Autosomal recessive |
| 3,[4] 2-5[7] | 615267 | IL17RD | IL17RD | 3p14.3 | Congenital hearing loss. | Autosomal recessive | |
| 2,[4] 2-5[7] | 611584 | SOX10 | SOX10 | 22q13.1 | Congenital hearing loss. | Waardenburg syndrome | Autosomal dominant |
| 2,[4] <2[7] | 614842 | KISS1 | KiSS-1 | 1q32.1 | Autosomal recessive | ||
| 2,[4] <2[7] | 614837 | KISS1R (GPR54) | GPR54 | 19p13.3 | Autosomal recessive | ||
| <2[7] | 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] | 615270 | FGF17 | FGF17 | 8p21.3 | Dandy–Walker syndrome | Autosomal dominant | |
| <2[4] | 164260 | LEP | LEP | 7q32.1 | Early onset of morbid obesity. | Autosomal recessive | |
| <2[4] | 601007 | LEPR | LEPR | 1p31.3 | Early onset of morbid obesity. | Autosomal recessive | |
| <2[4] | 162150 | PCSK1 | PCSK1 | 5q15 | Early onset of morbid obesity. | Autosomal recessive | |
| Rare,[4] 1 report[7][8] | 616030 | FEZF1 | FEZF1 | 7q31.32 | Autosomal recessive | ||
| Rare,[4] 2 reports [7][9][10][11] | 616031 | CCDC141 | CCDC141 | 2q31.2 | Unknown | ||
| Rare,[4] <2[7] | 614897 | SEMA3A | SEMA3A | 7q21.11 | Autosomal dominant | ||
| 1 report[7] | 608166 | SEMA3E | SEMA3E | 7q21.11 | CHARGE syndrome | Autosomal dominant | |
| Rare[4] | 607961 | SEMA7A | SEMA7A | 15q24.1 | Autosomal dominant | ||
| Rare,[4] <2[7] | 614880 | HS6ST1 | HS6ST1 | 2q14.3 | Cleft lip and / or cleft palate. Skeletal anomalies. | Autosomal dominant | |
| Rare,[4] 1 report[7] | 614858 | WDR11 | WDR11 | 10q26.12 | Combined pituitary hormone deficiency. | Autosomal dominant | |
| Rare[4] | 614838 | NELF (NSMF) | NELF | 9q34.3 | Autosomal dominant | ||
| Rare[4] | 617351 | IGSF10 | IGSF10 | 3q24 | Autosomal dominant | ||
| Rare,[4] <2[7] | 614841 | GNRH1 | GNRH1 | 8p21.2 | Autosomal recessive | ||
| Rare,[4] <2[7] | 614839 | TAC3 | TAC3 | 12q3 | Autosomal recessive | ||
| Rare,[4] 5[7] | 614840 | TACR3 | TACR3 | 4q24 | Autosomal recessive | ||
| Rare[4] | 611744 | OTUD4 | OTUD4 | 4q31.21 | Cerebellar ataxia. | Gordon Holmes syndrome | Autosomal recessive |
| Rare[4] | 609948 | RNF216 | RNF216 | 7p22.1 | Cerebellar ataxia. | Gordon Holmes syndrome | Autosomal recessive |
| Rare[4] | 603197 | PNPLA6 | PNPLA6 | 19p13.2 | Cerebellar ataxia. | Gordon Holmes syndrome | Autosomal recessive |
| 1 report[7] | 109135 | AXL | AXL | 19q13.2 | Unknown | ||
| Rare[4] | 612186 | DMXL2 | DMXL2 | 15q21.2 | Polyendocrine deficiencies and polyneuropathy. | Autosomal recessive | |
| Rare[4] | 300473 | NR0B1 (DAX1) | NR0B1 | Xp21.2 | Adrenal hypoplasia. | x-linked | |
| 1 report[7] | 602748 | DUSP6 | DUSP6 | 12q21.33 | Autosomal dominant | ||
| 1 report[7] | 614366 | POLR3B | POLR3B | 12q23.3 | Autosomal recessive | ||
| 1 report[7] | 615266 | SPRY4 | SPRY4 | 5q31.3 | Autosomal dominant | ||
| 1 report[7] | 615271 | FLRT3 | FLRT3 | 20p12.1 | Autosomal dominant | ||
| 1 report[7] | 617264 | SRA1 | SRA1 | 19q13.33 | Unknown | ||
| Rare[4] | 601802 | HESX1 | HESX1 | 3p14.3 | Septo-optic dysplasia. Combined pituitary hormone deficiency. | Autosomal recessive and dominant |
See also
[edit]References
[edit]- ^ Layman L. (2013). "Clinical Testing for Kallmann Syndrome". J Clin Endocrinol Metab. 98 (5): 1860–1862. doi:10.1210/jc.2013-1624. PMC 3644595. PMID 23650337.
- ^ Valdes-Socin H, Rubio Almanza M, Tomé Fernández-Ladreda M, Debray FG, Bours V, Beckers A (2014). "Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes". Front Endocrinol (Lausanne). 5 (109): 109. doi:10.3389/fendo.2014.00109. PMC 4088923. PMID 25071724.
- ^ Mitchell AL, Dwyer A, Pitteloud N, Quinton R (2011). "Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory". Trends Endocrinol. Metab. 22 (7): 249–58. doi:10.1016/j.tem.2011.03.002. PMID 21511493. S2CID 23578201.
- ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag Lima Amato LG, Latronico AC, Gontijo Silveira LF (2017). "Molecular and Genetic Aspects of Congenital Isolated Hypogonadotropic Hypogonadism". Endocrinol Metab Clin North Am. 46 (2): 283–303. doi:10.1016/j.ecl.2017.01.010. PMID 28476224.
- ^ Boehm U, Bouloux PM, Dattani MT, et al. (2015). "Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism-pathogenesis, diagnosis and treatment". Nat Rev Endocrinol. 11 (Jul 21): 547–64. doi:10.1038/nrendo.2015.112. hdl:11567/821921. PMID 26194704.
- ^ Vezzoli V, Duminuco P, Bassi I, Guizzardi F, Persani L, Bonomi M (2016). "The complex genetic basis of congenital hypogonadotropic hypogonadism". Minerva Endocrinol. 41 (2): 223–39. PMID 26934720.
- ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa 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; Bicakci, YK; Mengen, E; Yuksel, B; Wray, S; Topaloglu, AK (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. PMC 4157145. PMID 25192046.
- ^ Hutchins, BI; Kotan, LD; Taylor-Burds, C; Ozkan, Y; Cheng, PJ; Gurbuz, F; Tiong, JD; Mengen, E; Yuksel, B; Topaloglu, AK; Wray, S (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. PMC 4870868. PMID 27014940.
- ^ Turan, I; Hutchins, BI; Hacihamdioglu, B; Kotan, LD; Gurbuz, F; Ulubay, A; Mengen, E; Yuksel, B; Wray, S; Topaloglu, AK (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. PMC 5470764. PMID 28324054.
- ^ Hou, Q; Wu, J; Zhao, Y; Wang, X; Jiang, F; Chen, DN; Zheng, R; Men, M; Li, JD (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. S2CID 219585992.