Table 1.
Congenital hypogonadotropic hypogonadism gene characteristics
| Gene name | Inheritance | Gene function contributing in symptoms | Clinical phenotype based on expert consensus (Boehm et al. 2015) and OMIM database | OMIM number ID or Ref |
|---|---|---|---|---|
| ANOS1 (KAL1) | XR, contributes to oligogenicity | Migration of GnRH neurons | Kallmann syndrome, CHH reversal | 308700 |
| AXL | AD | Migration of GnRH neurons | Kallmann syndrome; CHH | Salian-Mehta et al. (2014) |
| BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12 | AD or AR | Maintenance and function of cilia (cell movement, perception of sensory input such as sight, hearing, and smell) | Bardet-Biedl syndrome 1–12 | 209900 |
| CHD7 | AD | Migration of GnRH neurons | Kallmann syndrome; CHH with or without reversal; CHARGE sy | 612370 |
| CPE | AR | As part of a syndrome | CHH, obesity, diabetes mellitus type 2 | Alsters et al. (2015) |
| DCAF17 | AR | As part of a syndrome | Woodhouse-Sakati syndrome | 241080 |
| DMXL2 | AD or AR | As part of a syndrome | CHH; PEPNS (polyendocrine deficiencies and polyneuropathies) | 616113 |
| DUSP6 | AD | Migration of GnRH neurons | CHH with or without anosmia | 615269 |
| FEZF1 | AR | Migration of GnRH neurons | Kallmann syndrome | 616030 |
| FGF17 | AD, contributes to oligogenicity | Hypothalamus/pituitary development | Kallmann syndrome; CHH; Dandy-Walker sy | 615270 |
| FGF8 | AD, contributes to oligogenicity | Hypothalamus/pituitary development,migration of GnRH neurons, neuroendocrine regulation | Kallmann syndrome; CHH; Combined pituitary hormone deficiency | 612702 |
| FGFR1 | AD, contributes to oligogenicity | Hypothalamus/pituitary development, neuroendocrine regulation | Kallmann syndrome; CHH with or without reversal; Combined pituitary hormone deficiency; Septo-optic dysplasia; Hartsfield sy; Split hand/foot malformation | 147950 |
| FLRT3 | AD | Migration of GnRH neurons | CHH with anosmia | 615271 |
| FSHB | AR | Hypothalamus/pituitary development | CHH without anosmia | 229070 |
| GLCE | AD, AR | Hypothalamus/pituitary development | KS, CHH | Stamou and Georgopoulos (2018) |
| GNRH1 | AR | neuroendocrine regulation | CHH | 614841 |
| GNRHR | AR, contributes to oligogenicity | Neuroendocrine regulation | CHH with or without reversal | 146110 |
| HDAC8 | XR | Transcriptional regulation, cell cycle progression and development | Cornelia de Lange syndrome 5 | 300882 |
| HESX1 | AD or AR | Hypothalamus/pituitary development | Kallmann syndrome; Combined pituitary hormone deficiency, Septo-optic dysplasia | 182230 |
| HFE | AD or AR | Controlling iron absorption by regulating the interaction of the transferrin receptor with transferrin | Hereditary hemochromatosis | 235200 |
| HS6ST1 | AD, contributes to oligogenicity | Migration of GnRH neurons | Kallmann syndrome; CHH with or without reversal | 614880 |
| IL17RD (SEF) | AD, AR or digenic dominant, contributes to oligogenicity | Migration of GnRH neurons | CHH with or without anosmia | 615267 |
| IRF2BPL (EAP1) | Not known | Neuroendocrine regulation | CHH | Mancini et al. (2019) |
| KISS1 | AR | neuroendocrine regulation | CHH | 614842 |
| KISS1R | AR, contributes to oligogenicity | Neuroendocrine regulation | CHH | 614837 |
| LEP | AR | Neuroendocrine regulation | CHH, obesity | Strobel et al. (1998) |
| LEPR | AR | Neuroendocrine regulation | CHH, obesity | Hannema et al. (2016) |
| LHB | AR | Hypothalamus/pituitary development | CHH with or without anosmia | 228300 |
| LHX3 | AR | Hypothalamus/pituitary development | Combined pituitary hormone deficiency | 221750 |
| NDN | AD | Neuroendocrine regulation | Prader-Willi syndrome | 176270 |
| NR0B1 (DAX1) | XR | Hypothalamus/pituitary development | CHH, congenital adrenal hypoplasia | 300200 |
| NSMF (NELF) | AD, contributes to oligogenicity | Migration of GnRH neurons | Kallmann syndrome; CHH with or without reversal | 614838 |
| OTUD4 | AR | As a deubiquitinase it negatively regulates inflammatory and pathogen recognition signaling in innate immune response | CHH; Gordon-Holmes sy | 212840 |
| PCSK1 | AR | Hypothalamus/pituitary development | CHH, obesity | 600955 |
| PNPLA6 | AR | Regulation of neurite outgrowth and process elongation during neuronal differentiation | CHH; Boucher-Neuhauser syndrome | 215470 |
| POLR3A | AR | As a DNA-dependent RNA polymerase it catalyzes the transcription of DNA into RNA | Leukodystrophy, hypomyelinating, seven, with or without oligodontia and/or hypogonadotropic hypogonadism | 607694 |
| POLR3B | AR | As a DNA-dependent RNA polymerase it catalyzes the transcription of DNA into RNA | Leukodystrophy, hypomyelinating, eight, with or without oligodontia and/or hypogonadotropic hypogonadism | 614381 |
| PROK2 | AD, contributes to oligogenicity | Migration of GnRH neurons | Kallmann syndrome; CHH | 610628 |
| PROKR2 | AD, contributes to oligogenicity | Migration of GnRH neurons | Kallmann syndrome; CHH with or without reversal; Combined pituitary hormone deficiency; Morning glory syndrome | 244200 |
| PROP1 | AR | Hypothalamus/pituitary development | Combined pituitary hormone deficiency | 262600 |
| RAB18 | AR | Eye and brain development, regulating membrane trafficking in organelles and transport vesicles | Warburg micro syndrome 3 | 614222 |
| RAB3GAP1 | AR | Eye and brain development, regulated exocytosis of neurotransmitters and hormones | Warburg micro syndrome 1 | 600118 |
| RAB3GAP2 | AR | Eye and brain development, regulated exocytosis of neurotransmitters and hormones | Martsolf syndrome (cataract, mental-retardation, hypogonadism) | 212720 |
| RBM28 | AR | Splicing regulator | Alopecia, neurologic defects, and endocrinopathy syndrome | 612079 |
| RNF216 | AR | Ubiquitination, protein degradation by the proteasome, regulation of TNF-, IL1- and NFKB signaling | CHH; Gordon-Holmes sy | 212840 |
| SEMA3A | AD, contributes to oligogenicity | Migration of GnRH neurons | Kallmann syndrome | 614897 |
| SEMA3E | AD | Migration of GnRH neurons | KS, CHH | Cariboni et al. (2015) |
| SEMA7A | contributes to oligogenicity | Migration of GnRH neurons | Kallmann syndrome; CHH | Känsäkoski et al. (2014) |
| SOX10 | AD | Hypothalamus/pituitary development | Kallmann syndrome; Waardenburg syndrome; PCWH syndrome (peripheral demyelinating neuropathy, central demyelination, Waardenburg syndrome, and Hirschsprung disease) | 611584 |
| SOX2 | AD | Hypothalamus/pituitary development | CHH, optic nerve hypoplasia and abnormalities of the central nervous system | 206900 |
| SOX3 | XR | Hypothalamus/pituitary development | CHH | Izumi et al. (2014) |
| SPRY4 | AD | Migration of GnRH neurons | Kallmann syndrome | 615266 |
| SRA1 | AD | Neuroendocrine regulation | CHH | Kotan et al. (2016) |
| STUB1 | AR | Ubiquitination, protein degradation by the proteasome | Spinocerebellar Ataxia 16, Autosomal Recessive | 615768 |
| TAC3 | AR, contributes to oligogenicity | Neuroendocrine regulation | CHH with or without reversal | 614839 |
| TACR3 | AR, contributes to oligogenicity | Neuroendocrine regulation | CHH with or without reversal | 614840 |
| TBC1D20 | AR | Regulation of vesicle-mediated transport, GTPase-activating protein specific for Rab1 and Rab2 | Warburg micro syndrome 4 | 615663 |
| TUBB3 | AD | Migration of GnRH neurons | “TUBB3 E410K syndrome” | Chew et al. (2013); Patel et al. (2017) |
| WDR11 | AD, contributes to oligogenicity | Migration of GnRH neurons | Kallmann syndrome; CHH with or without reversal; Combined pituitary hormone deficiency | 614858 |