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

• Kallmann syndrome
• Hypogonadotropic hypogonadism
• GnRH
• Isolated hypogonadotropic hypogonadism

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. hdl:11567/821921. 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.