Genetics of GnRH deficiency conditions
File:The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism.jpg]]
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.{{cite journal |author=Layman L. |title=Clinical Testing for Kallmann Syndrome. |journal=J Clin Endocrinol Metab |volume=98 |issue=5 |pages=1860–1862 |year=2013 |pmid=23650337 |doi=10.1210/jc.2013-1624 |pmc=3644595}}{{cite journal |vauthors=Valdes-Socin H, Rubio Almanza M, Tomé Fernández-Ladreda M, Debray FG, Bours V, Beckers A|title=Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes. |journal=Front Endocrinol (Lausanne) |volume=5 |issue=109 |pages= 109|year=2014 |pmc=4088923 |doi=10.3389/fendo.2014.00109 |pmid=25071724|doi-access=free }}
The number of genes known to cause cases of KS/CHH is still increasing.{{cite journal |vauthors=Mitchell AL, Dwyer A, Pitteloud N, Quinton R|title=Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory. |journal=Trends Endocrinol. Metab. |volume=22 |issue=7 |pages=249–58 |year=2011 |pmid=21511493 |doi=10.1016/j.tem.2011.03.002|s2cid=23578201 }} In addition, it is thought that some cases of KS/CHH are caused by two separate gene defects occurring at the same time.{{cite journal |vauthors=Lima Amato LG, Latronico AC, Gontijo Silveira LF|title=Molecular and Genetic Aspects of Congenital Isolated Hypogonadotropic Hypogonadism |journal=Endocrinol Metab Clin North Am |volume=46 |issue=2 |pages=283–303 |year=2017 |pmid=28476224 |doi=10.1016/j.ecl.2017.01.010}}
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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.{{cite journal |vauthors=Boehm U, Bouloux PM, Dattani MT, etal |title=Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism-pathogenesis, diagnosis and treatment. |journal=Nat Rev Endocrinol |volume= 11|issue=Jul 21 |pages= 547–64|year=2015 |pmid=26194704 |doi=10.1038/nrendo.2015.112|doi-access=free |hdl=11567/821921 |hdl-access=free }} Between 35 and 45% of cases of KS/CHH have an unknown genetic cause.{{cite journal |vauthors=Vezzoli V, Duminuco P, Bassi I, Guizzardi F, Persani L, Bonomi M|title=The complex genetic basis of congenital hypogonadotropic hypogonadism |journal=Minerva Endocrinol |volume=41 |issue=2 |pages=223–39 |year=2016 |pmid=26934720 }}
| class="wikitable" | |
| Prevalence (%)
! OMIM ! Name ! Gene ! Locus ! Clinical features ! Syndromes associated ! Inheritance pattern | |
|---|---|
| 5, 5-10{{cite journal |author=Balasubramanian R, Crowley WF Jr |title=Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency |journal=SourceGeneReviews |year=2017 |pmid=20301509 }}
|{{OMIM|308700 | none}}
|ANOS1 (KAL1) |Xp22.3 |Anosmia. Bimanual synkinesis. Renal agenesis. | |x-linked |
| 10
|{{OMIM|147950 | none}}
|KAL2 |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. |Autosomal dominant |
| 6-16, 5-10
|{{OMIM|146110 | none}}
|GNRHR |4q13.2 | | |Autosomal recessive |
| 6, 5-10
|{{OMIM|612370 | none}}
|CHD7 |CHD7 |8q12.2 |Congenital hearing loss. Semicircular canal hypoplasia. |Autosomal dominant |
| 3-6, <2
|{{OMIM|610628 | none}}
|KAL4 |3p13 | | |Autosomal recessive |
| 3-6, 5
|{{OMIM|244200 | none}}
|KAL3 |20p12.3 |Combined pituitary hormone deficiency. |Autosomal recessive |
| 3, 2-5
|{{OMIM|615267 | none}}
|IL17RD |3p14.3 | |Autosomal recessive |
| 2, 2-5
|{{OMIM|611584 | none}}
|SOX10 |22q13.1 |Autosomal dominant |
| 2, <2
|{{OMIM|614842 | none}}
|KISS1 |1q32.1 | | |Autosomal recessive |
| 2, <2
|{{OMIM|614837 | none}}
| KISS1R (GPR54) |19p13.3 | | |Autosomal recessive |
| <2
|{{OMIM|612702 | none}}
|FGF8 |FGF8 |10q24.32 |Cleft lip and / or cleft palate. Skeletal anomomolies. Bimanual synkinesis. Combined pituitary hormone deficiency. | |Autosomal dominant |
| <2, 1 report
|{{OMIM|615270 | none}}
|FGF17 |8p21.3 | |Autosomal dominant |
| <2
|{{OMIM|164260 | none}}
|LEP |LEP |7q32.1 |Early onset of morbid obesity. | |Autosomal recessive |
| <2
|{{OMIM|601007 | none}}
|LEPR |LEPR |1p31.3 |Early onset of morbid obesity. | |Autosomal recessive |
| <2
|{{OMIM|162150 | none}}
|PCSK1 |5q15 |Early onset of morbid obesity. | |Autosomal recessive |
| Rare, 1 report{{cite journal |last1=Kotan |first1=LD |last2=Hutchins |first2=BI |last3=Ozkan |first3=Y |last4=Demirel |first4=F |last5=Stoner |first5=H |last6=Cheng |first6=PJ |last7=Esen |first7=I |last8=Gurbuz |first8=F |last9=Bicakci |first9=YK |last10=Mengen |first10=E |last11=Yuksel |first11=B |last12=Wray |first12=S |last13=Topaloglu |first13=AK |title=Mutations in FEZF1 cause Kallmann syndrome. |journal=American Journal of Human Genetics |date=4 September 2014 |volume=95 |issue=3 |pages=326–31 |doi=10.1016/j.ajhg.2014.08.006 |pmid=25192046|pmc=4157145 }}
|{{OMIM|616030 | none}}
|FEZF1 |7q31.32 | | |Autosomal recessive |
| Rare, 2 reports {{cite journal |last1=Hutchins |first1=BI |last2=Kotan |first2=LD |last3=Taylor-Burds |first3=C |last4=Ozkan |first4=Y |last5=Cheng |first5=PJ |last6=Gurbuz |first6=F |last7=Tiong |first7=JD |last8=Mengen |first8=E |last9=Yuksel |first9=B |last10=Topaloglu |first10=AK |last11=Wray |first11=S |title=CCDC141 Mutation Identified in Anosmic Hypogonadotropic Hypogonadism (Kallmann Syndrome) Alters GnRH Neuronal Migration. |journal=Endocrinology |date=May 2016 |volume=157 |issue=5 |pages=1956–66 |doi=10.1210/en.2015-1846 |pmid=27014940|pmc=4870868 }}{{cite journal |last1=Turan |first1=I |last2=Hutchins |first2=BI |last3=Hacihamdioglu |first3=B |last4=Kotan |first4=LD |last5=Gurbuz |first5=F |last6=Ulubay |first6=A |last7=Mengen |first7=E |last8=Yuksel |first8=B |last9=Wray |first9=S |last10=Topaloglu |first10=AK |title=CCDC141 Mutations in Idiopathic Hypogonadotropic Hypogonadism. |journal=The Journal of Clinical Endocrinology and Metabolism |date=1 June 2017 |volume=102 |issue=6 |pages=1816–1825 |doi=10.1210/jc.2016-3391 |pmid=28324054|pmc=5470764 }}{{cite journal |last1=Hou |first1=Q |last2=Wu |first2=J |last3=Zhao |first3=Y |last4=Wang |first4=X |last5=Jiang |first5=F |last6=Chen |first6=DN |last7=Zheng |first7=R |last8=Men |first8=M |last9=Li |first9=JD |title=Genotypic and phenotypic spectrum of CCDC141 variants in a Chinese cohort with congenital hypogonadotropic hypogonadism. |journal=European Journal of Endocrinology |date=September 2020 |volume=183 |issue=3 |pages=245–254 |doi=10.1530/EJE-19-1018 |pmid=32520725|s2cid=219585992 |doi-access=free }}
|{{OMIM|616031 | none}}
|CCDC141 |2q31.2 | | |Unknown |
| Rare, <2
|{{OMIM|614897 | none}}
|SEMA3A |7q21.11 | | |Autosomal dominant |
| 1 report
|{{OMIM|608166 | none}}
|SEMA3E |7q21.11 | |Autosomal dominant |
| Rare
|{{OMIM|607961 | none}}
|SEMA7A |15q24.1 | | |Autosomal dominant |
| Rare, <2
|{{OMIM|614880 | none}}
|HS6ST1 |2q14.3 |Cleft lip and / or cleft palate. Skeletal anomalies. | |Autosomal dominant |
| Rare, 1 report
|{{OMIM|614858 | none}}
|WDR11 |10q26.12 |Combined pituitary hormone deficiency. | |Autosomal dominant |
| Rare
|{{OMIM|614838 | none}}
|NELF (NSMF) |NELF |9q34.3 | | |Autosomal dominant |
| Rare
|{{OMIM|617351 | none}}
|IGSF10 |3q24 | | |Autosomal dominant |
| Rare, <2
|{{OMIM|614841 | none}}
|GNRH1 |8p21.2 | | |Autosomal recessive |
| Rare, <2
|{{OMIM|614839 | none}}
|TAC3 |TAC3 |12q3 | | |Autosomal recessive |
| Rare, 5
|{{OMIM|614840 | none}}
|TACR3 |4q24 | | |Autosomal recessive |
| Rare
|{{OMIM|611744 | none}}
|OTUD4 |4q31.21 |Autosomal recessive |
| Rare
|{{OMIM|609948 | none}}
|RNF216 |7p22.1 |Autosomal recessive |
| Rare
|{{OMIM|603197 | none}}
|PNPLA6 |19p13.2 |Autosomal recessive |
| 1 report
|{{OMIM|109135 | none}}
|AXL |AXL |19q13.2 | | |Unknown |
| Rare
|{{OMIM|612186 | none}}
|DMXL2 |15q21.2 |Polyendocrine deficiencies and polyneuropathy. | |Autosomal recessive |
| Rare
|{{OMIM|300473 | none}}
|NR0B1 (DAX1) |Xp21.2 | |x-linked |
| 1 report
|{{OMIM|602748 | none}}
|DUSP6 |12q21.33 | | |Autosomal dominant |
| 1 report
|{{OMIM|614366 | none}}
|POLR3B |12q23.3 | | |Autosomal recessive |
| 1 report
|{{OMIM|615266 | none}}
|SPRY4 |5q31.3 | | |Autosomal dominant |
| 1 report
|{{OMIM|615271 | none}}
|FLRT3 |20p12.1 | | |Autosomal dominant |
| 1 report
|{{OMIM|617264 | none}}
|SRA1 |SRA1 |19q13.33 | | |Unknown |
| Rare
|{{OMIM|601802 | none}}
|HESX1 |3p14.3 |Septo-optic dysplasia. Combined pituitary hormone deficiency. | |Autosomal recessive and dominant |