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.

The number of genes known to cause cases of KS/CHH is still increasing. In addition, it is thought that some cases of KS/CHH are caused by two separate gene defects occurring at the same time. __TOC__ 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. Between 35 and 45% of cases of KS/CHH have an unknown genetic cause.

Prevalence (%) OMIM Name Gene Locus Clinical features Syndromes associated Inheritance pattern5, 5-10ANOS1 (KAL1)ANOS1Xp22.3Anosmia. Bimanual synkinesis. Renal agenesis. x-linked10KAL2FGFR1 8p11.23Cleft lip and / or cleft palate. Septo-optic dysplasia. Skeletal anomomalies. Bimanual synkinesis. Hand / foot malformations such as ectrodactyly. Combined pituitary hormone deficiency.Hartsfield syndromeAutosomal dominant6-16, 5-10GNRHRGNRHR 4q13.2Autosomal recessive6, 5-10CHD7CHD78q12.2Congenital hearing loss. Semicircular canal hypoplasia.CHARGE syndromeAutosomal dominant3-6, <2KAL4PROK23p13 Autosomal recessive3-6, 5KAL3PROKR220p12.3Combined pituitary hormone deficiency.Morning Glory syndromeAutosomal recessive3, 2-5IL17RDIL17RD3p14.3Congenital hearing loss.Autosomal recessive2, 2-5SOX10SOX1022q13.1Congenital hearing loss.Waardenburg syndromeAutosomal dominant2, <2 KISS1KiSS-11q32.1 Autosomal recessive2, <2 KISS1R (GPR54)GPR5419p13.3 Autosomal recessive<2FGF8FGF810q24.32Cleft lip and / or cleft palate. Skeletal anomomolies. Bimanual synkinesis. Combined pituitary hormone deficiency.Autosomal dominant<2, 1 reportFGF17FGF178p21.3Dandy–Walker syndromeAutosomal dominant<2LEPLEP7q32.1Early onset of morbid obesity.Autosomal recessive<2LEPRLEPR1p31.3Early onset of morbid obesity.Autosomal recessive<2PCSK1PCSK15q15Early onset of morbid obesity.Autosomal recessiveRare, 1 reportFEZF1FEZF17q31.32 Autosomal recessiveRare, 2 reports CCDC141CCDC1412q31.2UnknownRare, <2SEMA3ASEMA3A7q21.11Autosomal dominant1 reportSEMA3ESEMA3E7q21.11CHARGE syndromeAutosomal dominantRareSEMA7ASEMA7A15q24.1Autosomal dominantRare, <2HS6ST1HS6ST12q14.3Cleft lip and / or cleft palate. Skeletal anomalies.Autosomal dominantRare, 1 reportWDR11WDR1110q26.12Combined pituitary hormone deficiency.Autosomal dominantRareNELF (NSMF)NELF9q34.3Autosomal dominantRareIGSF10IGSF103q24Autosomal dominantRare, <2GNRH1GNRH18p21.2Autosomal recessiveRare, <2TAC3TAC312q3 Autosomal recessiveRare, 5TACR3 TACR34q24 Autosomal recessiveRareOTUD4OTUD44q31.21Cerebellar ataxia.Gordon Holmes syndromeAutosomal recessiveRareRNF216RNF2167p22.1Cerebellar ataxia.Gordon Holmes syndromeAutosomal recessiveRarePNPLA6PNPLA619p13.2Cerebellar ataxia.Gordon Holmes syndromeAutosomal recessive1 reportAXLAXL19q13.2UnknownRareDMXL2DMXL215q21.2Polyendocrine deficiencies and polyneuropathy. Autosomal recessiveRareNR0B1 (DAX1)NR0B1Xp21.2Adrenal hypoplasia. x-linked1 reportDUSP6DUSP612q21.33Autosomal dominant1 reportPOLR3BPOLR3B12q23.3Autosomal recessive1 reportSPRY4SPRY45q31.3Autosomal dominant1 reportFLRT3FLRT320p12.1Autosomal dominant1 reportSRA1SRA119q13.33UnknownRareHESX1HESX13p14.3Septo-optic dysplasia. Combined pituitary hormone deficiency.Autosomal recessive and dominant

See also Kallmann syndrome Hypogonadotropic hypogonadism GnRH Isolated hypogonadotropic hypogonadism

References