| Gene (HGNC symbol) | Protein/role (ion channel/synaptic) | Evidence for association (classic paper/review + context IDs) | Example pathogenic variants or mutation classes (as reported) | Inheritance notes/penetrance if available | Mechanistic theme |
|---|---|---|---|---|---|
| SCN1B | Voltage-gated sodium channel β1 subunit; channel modulatory subunit | First GEFS+ gene discovery in a large family: Wallace et al. 1998; also summarized in Wallace et al. 2001 and later commentary/review (pqac-00000020, pqac-00000019, pqac-00000015) | C121W / p.Cys121Trp; coding mutation at nt 387 C>G; loss-of-function β1 modulation reported (pqac-00000009, pqac-00000019, pqac-00000015) | Major autosomal dominant gene in GEFS+ pedigrees; classic pedigree analysis estimated ~60% penetrance for GEFS+ families, with incomplete penetrance/variable expressivity emphasized in later reviews (pqac-00000013, pqac-00000015) | Impaired β1 modulation of Na+ channel gating/inactivation leading to increased sodium influx, membrane depolarization, and neuronal hyperexcitability (pqac-00000009, pqac-00000019) |
| SCN1A | Voltage-gated sodium channel α1 / Nav1.1 pore-forming subunit | GEFS2 locus and SCN1A association established in 2000–2001 papers; frequency and phenotype spectrum reviewed in 2001 and 2024 papers (pqac-00000019, pqac-00000010, pqac-00000017) | T875M, R1648H; D188V, V1353L, I1656M; W1204R; missense variants enriched in GEFS+; truncating variants more often associated with Dravet syndrome (pqac-00000019, pqac-00000010, pqac-00000030) | Familial GEFS+ is typically autosomal dominant with incomplete penetrance and phenotypic heterogeneity; SCN1A mutations accounted for ~5.6% of 53 unrelated GEFS+ index cases and combined SCN1A/SCN1B mutations for ~17% of familial cases in one 2001 series (pqac-00000019) | Altered channel gating/inactivation, especially S4 voltage-sensor effects; reduced inhibitory interneuron excitability is emphasized in modern Nav1.1 literature (pqac-00000019, pqac-00000028) |
| GABRG2 | GABA-A receptor γ2 subunit; ligand-gated chloride channel subunit | Major GEFS+ gene in recent review; listed among main causative genes in 2025 commentary and Open Targets evidence (pqac-00000017, pqac-00000015, pqac-00000000) | Missense (c.983A>T, c.245G>A, p.Met199Val), nonsense (R136*, Q390*, W429*), frameshift (c.1329delC, p.Val462fs*33, p.Pro59fs*12), point (P83S), splice-site (IVS6+2T>G); p.Arg82Gln highlighted in polygenic modifier study (pqac-00000017, pqac-00000015, pqac-00000021) | Often segregates in large autosomal dominant GEFS+ families; variable expressivity and incomplete/Mendelian complexity discussed, with environmental and modifier effects noted (pqac-00000017, pqac-00000018, pqac-00000015) | Reduced GABA-A receptor function via impaired receptor trafficking, altered surface expression, ER stress/endocytosis-related defects, and diminished inhibitory synaptic transmission (pqac-00000017, pqac-00000018, pqac-00000021) |
| STX1B | Syntaxin-1B; synaptic vesicle exocytosis / presynaptic release machinery | Supported in Open Targets/ClinGen-linked evidence and 2024 mouse-model work for fever-associated epilepsy/GEFS+ spectrum (pqac-00000000, pqac-00000003, pqac-00000030) | Specific human variant examples not retrieved in current evidence set; heterozygous knockout/model evidence available (pqac-00000003, pqac-00000030) | Familial cases with variable expressivity are reported in the broader literature, but penetrance figures were not retrieved in current evidence | Synaptic transmission defect affecting vesicle release and network excitability; fever sensitivity supported by Stx1b model work (pqac-00000003, pqac-00000030) |
| SLC32A1 | Vesicular inhibitory amino acid transporter (VIAAT/VGAT); loads GABA/glycine into synaptic vesicles | Supported by Open Targets disease-target evidence and cited literature for GEFS+ association (pqac-00000000) | Specific variants not detailed in retrieved full-text evidence; association supported by PMID-linked target evidence (PMID 34038384 in Open Targets evidence row) (pqac-00000000) | Inheritance/penetrance not retrieved in current evidence | Impaired vesicular loading of inhibitory neurotransmitters, reducing inhibitory synaptic transmission (pqac-00000000) |
| HCN1 | Hyperpolarization-activated cyclic nucleotide-gated channel 1; pacemaker cation channel | Supported by Open Targets disease-target evidence and cited literature for GEFS+ (pqac-00000000) | Specific variants not described in retrieved excerpts; literature support includes PMID-linked evidence (e.g., 30351409 in Open Targets) (pqac-00000000) | Inheritance/penetrance not retrieved in current evidence | Altered Ih/pacemaker conductance and neuronal excitability (pqac-00000000) |
| HCN2 | Hyperpolarization-activated cyclic nucleotide-gated channel 2; pacemaker cation channel | Supported by Open Targets disease-target evidence and cited literature for GEFS+ (pqac-00000000) | Specific variants not described in retrieved excerpts; literature support includes PMID-linked evidence in Open Targets row (pqac-00000000) | Inheritance/penetrance not retrieved in current evidence | Altered Ih-mediated rhythmicity/excitability contributing to seizure susceptibility (pqac-00000000) |
| SCN9A | Voltage-gated sodium channel α subunit Nav1.7 | Supported by Open Targets disease-target evidence; also listed among additional implicated genes in commentary/review (pqac-00000000, pqac-00000004) | Specific GEFS+-causal variants not detailed in retrieved excerpts (pqac-00000000) | Inheritance/penetrance not retrieved in current evidence | Sodium channel dysfunction increasing neuronal excitability; exact GEFS+-specific mechanism not detailed in retrieved excerpts (pqac-00000000, pqac-00000004) |
| PRRT2 | Proline-rich transmembrane protein 2; synaptic/exocytosis-associated protein | Supported by Open Targets disease-target evidence for GEFS+ (pqac-00000000) | Specific variants not detailed in retrieved excerpts; literature support includes PMIDs 25522171 and 28007585 in Open Targets evidence (pqac-00000000) | Inheritance/penetrance not retrieved in current evidence | Likely synaptic release/exocytosis dysfunction affecting neuronal network stability (pqac-00000000) |
| GABRD | GABA-A receptor δ subunit; extrasynaptic inhibitory receptor subunit | Supported by Open Targets disease-target evidence for Orphanet GEFS+ and cited literature (pqac-00000000) | Specific variants not detailed in retrieved excerpts; literature support includes PMIDs 15115768, 29785705, 34633442 in Open Targets evidence (pqac-00000000) | Inheritance/penetrance not retrieved in current evidence | Reduced tonic GABAergic inhibition via δ-subunit dysfunction, promoting hyperexcitability (pqac-00000000) |


*Table: This table summarizes the principal genes currently supported in the retrieved evidence for GEFS+ and the main mechanistic themes linking them to disease. It combines classic discovery papers with recent reviews and target-association evidence to show how sodium-channel, GABAergic, and synaptic genes converge on neuronal hyperexcitability.*