Table 2.
Candidates involved in GnRH neuron development mutated in human subjects. Names of genes shown to be mutated in probands with KS or nIHH with mode of inheritance, penetration, frequency of occurrence, phenotype and documentation of digenicity.
| Candidate | Pattern of inheritance | Phenotype | Frequency in IHH patients | Digenicity |
|---|---|---|---|---|
| KAL-1 (Anosmin) | X-linked | Anosmic, complete penetrance | 5-10% | Yes |
| FGF8 (KAL-6) | AD | Anosmic, normosmic NRP, FPP | 2% | Yes |
| FGFR1 (KAL-2) | AD | Variable expressivity AP, DP, PP | 10% | Yes |
| PROK2 (KAL-4) | AD, AR | Anosmic, normosmic Incomplete penetrance | 2% | Yes |
| PROKR2 (KAL-3) | AD, AR | Anosmic, normosmic Incomplete penetrance | 4% | Yes |
| CHD7 (KAL-5) | AD | Anosmic, normosmic CHARGE syndrome | 5% | Not reported |
| NELF | AR | Hyposmic | <1% | Yes |
| KISSR (GPR54) | AR | Normosmic | 2% | No |
| Axl | sporadic | Anosmic,normosmic | ? | Yes |
AD-autosomal dominant; AR-autosomal recessive; AP-absent puberty, DP-delayed puberty, DP-delayed pubery, NRP-normal reproductive phenotype, FPP-fully penetrant phenotype
CHARGE syndrome: coloboma, heart abnormalities, choanal atresia, retardation of growth and development, genital hypoplasia and ear abnormalities
KAL 1 – Kallmann 1; FGF8- Fibroblast growth factor 8; FGFR1- Fibroblast growth factor receptor 1; PROK2-Prokineticin 2; PROKR2-Prokineticin 2 receptor; CHD7- Chromodomain helicase DNA binding protein 7; NELF- Nasal embryonic LHRH factor; KISSR- Kisspeptin receptor