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 genetic and molecular basis of idiopathic hypogonadotropic hypogonadism

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] 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

References
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  2. 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.
  3. 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.
  4. 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.
  5. 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. PMID 26194704.
  6. 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.
  7. Balasubramanian R, Crowley WF Jr (2017). "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency". SourceGeneReviews. PMID 20301509.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
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