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] __TOC__
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, 5-10[7] | ANOS1 (KAL1) | ANOS1 | Xp22.3 | Anosmia. Bimanual synkinesis. Renal agenesis. | x-linked | |||
| 10 | 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. | Hartsfield syndrome | Autosomal dominant | |||
| 6-16, 5-10 | GNRHR | 4q13.2 | Autosomal recessive | |||||
| 6, 5-10 | CHD7 | CHD7 | 8q12.2 | Congenital hearing loss. Semicircular canal hypoplasia. | CHARGE syndrome | Autosomal dominant | ||
| 3-6, <2 | KAL4 | PROK2 | 3p13 | Autosomal recessive | ||||
| 3-6, 5 | KAL3 | PROKR2 | 20p12.3 | Combined pituitary hormone deficiency. | Morning Glory syndrome | Autosomal recessive | ||
| 3, 2-5 | IL17RD | IL17RD | 3p14.3 | Congenital hearing loss. | Autosomal recessive | |||
| 2, 2-5 | SOX10 | SOX10 | 22q13.1 | Congenital hearing loss. | Waardenburg syndrome | Autosomal dominant | ||
| 2, <2 | KISS1 | KiSS-1 | 1q32.1 | Autosomal recessive | ||||
| 2, <2 | KISS1R (GPR54) | GPR54 | 19p13.3 | Autosomal recessive | ||||
| <2 | FGF8 | FGF8 | 10q24.32 | Cleft lip and / or cleft palate. Skeletal anomomolies. Bimanual synkinesis. Combined pituitary hormone deficiency. | Autosomal dominant | |||
| <2, 1 report | FGF17 | FGF17 | 8p21.3 | Dandy–Walker syndrome | Autosomal dominant | |||
| <2 | LEP | LEP | 7q32.1 | Early onset of morbid obesity. | Autosomal recessive | |||
| <2 | LEPR | LEPR | 1p31.3 | Early onset of morbid obesity. | Autosomal recessive | |||
| <2 | PCSK1 | PCSK1 | 5q15 | Early onset of morbid obesity. | Autosomal recessive | |||
| Rare, 1 report[8] | FEZF1 | FEZF1 | 7q31.32 | Autosomal recessive | ||||
| Rare, 2 reports [9] [10] [11] | CCDC141 | CCDC141 | 2q31.2 | Unknown | ||||
| Rare, <2 | SEMA3A | SEMA3A | 7q21.11 | Autosomal dominant | ||||
| 1 report | SEMA3E | SEMA3E | 7q21.11 | CHARGE syndrome | Autosomal dominant | |||
| Rare | SEMA7A | SEMA7A | 15q24.1 | Autosomal dominant | ||||
| Rare, <2 | HS6ST1 | HS6ST1 | 2q14.3 | Cleft lip and / or cleft palate. Skeletal anomalies. | Autosomal dominant | |||
| Rare, 1 report | WDR11 | WDR11 | 10q26.12 | Combined pituitary hormone deficiency. | Autosomal dominant | |||
| Rare | NELF (NSMF) | NELF | 9q34.3 | Autosomal dominant | ||||
| Rare | IGSF10 | IGSF10 | 3q24 | Autosomal dominant | ||||
| Rare, <2 | GNRH1 | GNRH1 | 8p21.2 | Autosomal recessive | ||||
| Rare, <2 | TAC3 | TAC3 | 12q3 | Autosomal recessive | ||||
| Rare, 5 | TACR3 | TACR3 | 4q24 | Autosomal recessive | ||||
| Rare | OTUD4 | OTUD4 | 4q31.21 | Cerebellar ataxia. | Gordon Holmes syndrome | Autosomal recessive | ||
| Rare | RNF216 | RNF216 | 7p22.1 | Cerebellar ataxia. | Gordon Holmes syndrome | Autosomal recessive | ||
| Rare | PNPLA6 | PNPLA6 | 19p13.2 | Cerebellar ataxia. | Gordon Holmes syndrome | Autosomal recessive | ||
| 1 report | AXL | AXL | 19q13.2 | Unknown | ||||
| Rare | DMXL2 | DMXL2 | 15q21.2 | Polyendocrine deficiencies and polyneuropathy. | Autosomal recessive | |||
| Rare | NR0B1 (DAX1) | NR0B1 | Xp21.2 | Adrenal hypoplasia. | x-linked | |||
| 1 report | DUSP6 | DUSP6 | 12q21.33 | Autosomal dominant | ||||
| 1 report | POLR3B | POLR3B | 12q23.3 | Autosomal recessive | ||||
| 1 report | SPRY4 | SPRY4 | 5q31.3 | Autosomal dominant | ||||
| 1 report | FLRT3 | FLRT3 | 20p12.1 | Autosomal dominant | ||||
| 1 report | SRA1 | SRA1 | 19q13.33 | Unknown | ||||
| Rare | HESX1 | HESX1 | 3p14.3 | Septo-optic dysplasia. Combined pituitary hormone deficiency. | Autosomal recessive and dominant |