| Gene (HGNC symbol) | Typical inheritance in KS | Biological role/mechanism (short) | Evidence (include abstract quote if present) | Key references (with DOI/URL) |
|---|---|---|---|---|
| **ANOS1** (formerly **KAL1**) | X-linked recessive; can contribute to oligogenic KS | Encodes anosmin-1; involved in olfactory axon/GnRH neuron development and migration from olfactory placode to hypothalamus | Review evidence lists **KAL1/ANOS1** among core KS genes and classifies it as X-linked; KS mechanistically “results from disturbed intrauterine migration of gonadotropin-releasing hormone (GnRH) neurons from the olfactory placode to the hypothalamus” (pqac-00000007, pqac-00000009). Laitinen et al. found **KAL1 mutations in 3 men** in the Finnish cohort (pqac-00000009). | Laitinen 2011, *Orphanet J Rare Dis* — https://doi.org/10.1186/1750-1172-6-41; Żak 2024 review (pqac-00000007, pqac-00000009) |
| **FGFR1** | Usually autosomal dominant; incomplete penetrance; also seen in oligogenic disease | FGF receptor controlling olfactory bulb development, GnRH neuron ontogeny/migration, craniofacial/dental development | Laitinen: “**a monoallelic mutation in FGFR1 underlies approximately 10% of KS cases**” and mutations were found in **all 5 women vs. 4/25 men** in their cohort (pqac-00000009). Chu 2023: “**autosomal dominant (FGFR1, FGF8, and CHD7...)**” and identified novel FGFR1 variants including pathogenic frameshift/CNV lesions (pqac-00000003). | Laitinen 2011 — https://doi.org/10.1186/1750-1172-6-41; Chu 2023 — https://doi.org/10.1186/s12958-023-01074-w |
| **FGF8** | Usually autosomal dominant; sometimes incomplete penetrance/oligogenic contribution | Ligand for FGFR1 pathway; critical for embryonic olfactory/GnRH neuronal development | Core KS reviews consistently include **FGF8** in dominant KS genetics and within the neurodevelopmental class of genes linked to anosmic CHH/KS (pqac-00000007, pqac-00000012, pqac-00000015). The FGFR1/FGF8 axis is repeatedly associated with craniofacial and dental phenotypes in KS (pqac-00000015). | Chu 2023 — https://doi.org/10.1186/s12958-023-01074-w; Stamou 2018 — https://doi.org/10.1016/j.metabol.2017.10.012 |
| **PROK2** | Usually autosomal recessive; may participate in digenic/oligogenic KS | Ligand in prokineticin signaling required for olfactory bulb morphogenesis and GnRH neuron migration/guidance | Gene lists from Finnish and later reviews include **PROK2** among canonical KS genes with AR inheritance patterns and possible oligogenicity (pqac-00000003, pqac-00000009, pqac-00000016). Sayed 2023 emphasizes CHH/KS complexity with “**di- and oligogenic, as well as classic monogenic, inheritance and incomplete penetrance**” (pqac-00000014). | Laitinen 2011 — https://doi.org/10.1186/1750-1172-6-41; Sayed 2023 — https://doi.org/10.1038/s41431-022-01261-0 |
| **PROKR2** | Often autosomal recessive or dominant with reduced penetrance; frequent digenic/oligogenic contributor | GPCR for PROK2; regulates olfactory bulb formation and GnRH neuron migration; variants can also affect broader neuroendocrine phenotypes | Martinez-Mayer 2023 abstract: “**Mice lacking Prokr2 have been shown to present abnormal olfactory bulb formation as well as defects in GnRH neuron migration. Patients carrying mutations in PROKR2 typically present hypogonadotropic hypogonadism, anosmia/hyposmia or Kallmann Syndrome**” (pqac-00000000). He 2023 found **PROKR2** heterozygous variants in both KS and nIHH; Kałużna 2021 reported oligogenic P/LP defects in **26%** of KS patients (pqac-00000005, pqac-00000011). | Martinez-Mayer 2023 — https://doi.org/10.3389/fendo.2023.1132787; He 2023 — https://doi.org/10.2147/ijgm.s430904; Kałużna 2021 — https://doi.org/10.3390/genes12060868 |
| **CHD7** | Usually autosomal dominant; variable expressivity; incomplete penetrance; oligogenic cases reported | Chromatin remodeler implicated in neural crest/olfactory/GnRH development; overlaps KS–CHARGE spectrum | Laitinen notes some KS patients show CHARGE-like features even without CHD7 mutation, supporting pathway overlap (pqac-00000003). He 2023 detected **CHD7** variants in both KS and nIHH; Sayed 2023 highlights incomplete penetrance and oligogenic inheritance in CHH panels (pqac-00000005, pqac-00000014). | Laitinen 2011 — https://doi.org/10.1186/1750-1172-6-41; He 2023 — https://doi.org/10.2147/ijgm.s430904; Sayed 2023 — https://doi.org/10.1038/s41431-022-01261-0 |
| **WDR11** | Usually autosomal dominant or oligogenic contributor; incomplete penetrance reported | Developmental regulator affecting GnRH neuronal development and hypothalamic-pituitary signaling | Included in canonical KS gene sets from Laitinen and later NGS studies (pqac-00000003, pqac-00000005). Kałużna 2021 showed that genes affecting “**GnRH neuron migration/development and hypothalamic-pituitary signaling**” contribute to clinical variability in KS, supporting WDR11 as a pathway gene (pqac-00000011). | Laitinen 2011 — https://doi.org/10.1186/1750-1172-6-41; He 2023 — https://doi.org/10.2147/ijgm.s430904; Kałużna 2021 — https://doi.org/10.3390/genes12060868 |
| **SOX10** | Usually autosomal dominant; can be syndromic; reduced penetrance/variable expressivity | Neural crest transcription factor; links KS with hearing/pigmentary phenotypes and olfactory/GnRH developmental defects | He 2023: “**a novel likely pathogenic variant in the SOX10 (c.429–1G>C) was considered to cause the KS phenotype**” (pqac-00000005). Żak 2024 also lists **SOX10** among implicated autosomal dominant genes and notes hearing/pigmentary manifestations in KS (pqac-00000000). | He 2023 — https://doi.org/10.2147/ijgm.s430904; Żak 2024 review (pqac-00000000) |
| **SEMA3A** | Likely autosomal dominant susceptibility/modifier gene; often oligogenic | Axon guidance cue influencing olfactory/GnRH neuron pathfinding | Żak 2024 lists **SEMA3A** among genes “under investigation” in KS (pqac-00000007). He 2023 includes **SEMA3A** among common IHH/KS genes in the NGS era (pqac-00000005). Kałużna 2021 places KS genes within the broader class of migration/guidance genes; Sayed 2023 highlights panel-based diagnosis amid oligogenicity/incomplete penetrance (pqac-00000011, pqac-00000014). | He 2023 — https://doi.org/10.2147/ijgm.s430904; Sayed 2023 — https://doi.org/10.1038/s41431-022-01261-0 |
| **RMST** (lncRNA) | Structural-disruption/LOF mechanism reported in isolated case; inheritance not yet established as classic Mendelian pattern | Long noncoding RNA regulating neural crest/GnRH ontogeny; affects downstream developmental genes | Stamou 2020 abstract: “**A novel deletion in RMST implicates the loss of function of a lncRNA as a unique cause of KS and suggests it plays a critical role in the ontogeny of GnRH neurons and puberty**” (pqac-00000000). In patient-derived cells, RMST reduction was associated with abnormal neural crest morphology and altered expression of **SOX2, PAX3, CHD7, TUBB3, MKRN3** (pqac-00000000). | Stamou 2020 — https://doi.org/10.1210/clinem/dgz011 |
| **Cross-gene architecture note** | Monogenic, digenic, and oligogenic inheritance; incomplete penetrance common | KS is genetically heterogeneous; neurodevelopmental and hypothalamic-pituitary pathway defects converge on GnRH deficiency plus olfactory dysfunction | Kałużna 2021 abstract: “**The prevalence of oligogenic P/LP defects in selected genes among KS patients was 26% (12/46)**” and P/LP variants were found in **43.5%** of the cohort (pqac-00000011). Sayed 2023: CHH genetics includes “**di- and oligogenic, as well as classic monogenic, inheritance and incomplete penetrance**” (pqac-00000014). Liu 2022: “**Approximately 40% of KS patients have one or several rare sequence variants that have been identified**” (pqac-00000016). | Kałużna 2021 — https://doi.org/10.3390/genes12060868; Sayed 2023 — https://doi.org/10.1038/s41431-022-01261-0; Liu 2022 — https://doi.org/10.1007/s43032-021-00638-8 |


*Table: This table summarizes the main genes implicated in Kallmann syndrome, their typical inheritance patterns, and the developmental mechanisms linking them to GnRH deficiency and olfactory dysfunction. It is useful for rapid comparison of core KS genes while highlighting oligogenicity and incomplete penetrance.*