Table 2.
Pathogenic and likely pathogenic variants in novel epileptic encephalopathy genes
| Proband (gender, study age) |
Gene | Protein change (Polyphen, SIFT)& |
Diagnosis | Seizures$ (age of onset) | EEG | Development prior to seizure onset |
Cognitive outcome (regression) |
|---|---|---|---|---|---|---|---|
| Pathogenic variants (de novo) | |||||||
| T38 (M, 17 yr) | CHD2 | Glu1412Glyfs*64 | MAE | At (12mth) FS, Ab, MJ-At, MJ, TC | 3.8 Hz GSW | mild delay, behavioral problems | moderate ID, ASD (no) |
| T18697 (F, 12 yr) | CHD2 | Arg121* | EE | MJ(12mth) NCS, T, TC, MAb | GPSW, MFD, GPFA, SSW | Normal | severe ID (yes) |
| T2608 (F, 29 yr) | CHD2 | Gly491Valfs*13 | LGS | aAb (12mth) At, MJ, NCS, SE, T, TC | SSW, MFD, DS, GPSW, PPR triggered MJ | Delayed | severe ID (yes) |
| T20240 (M, 12 yr) | CHD2 | Arg1644Lysfs*22 | MAE | At (2y) MJ, SE, TC | DS, GPSW, 2.5 Hz GSW | Normal | severe ID (yes) T17756 |
| T17756 (M, 15 yr) | CHD2 | Trp548Arg (1, 0) | EE | TC (3y) FDS, H, MJ | GSW, MFD, DS | Delayed | Moderate ID (yes) |
| T18431 (M, 2.5 yr) | CHD2 | Leu823Pro (0.999, 0) | EE | FDS, MJ (2.5y) MJ-Ab, T | GSW, GPSW, MFD | Delayed | Severe ID, ASD (yes) |
| T15923 (F, 26 yr) | SYNGAP1 | Trp267* | EE | aAb(3y) At, Aura, FDS, MJ | SSW, MFD | Delayed | Severe ID, ASD (yes) |
| T2528 (M, 26 yr) | SYNGAP1 | Gln702* | EE | FS (18mth) Ab, Aura, FDS, MJ, NCS, TC | SSW, bi-occipital ED, DS | Delayed | Moderate ID (yes) |
| T1898 (F, 20 yr) | MBD5 | Thr157Glnfs*4 | EE | TC (6mth) Ab, FDS, Focal,,T | GPSW, MFD, DS | Delayed | Severe ID, ASD (no) |
| T20719 (M, 2.5 yr) | GABRG2 | Arg323Gln (0.998,0) | MAE | FS (8mth) Ab. At, MJ, TC | Normal | Normal | Normal (yes) |
| T23549 (F, 3.5 yr) | MEF2C | Cys39Arg (0.998, 0) | EE | FS (13mth) Ab, SE, TC | MFD, DS | Delayed | Severe ID, ASD (yes) |
| T18044+ (M, 4 yr) | MEF2C | *464Sext*? | EE | H (4 mth) Ab, At, focal, IS, MJ, TC | Mod Hyps, MFD | Normal | ID (no) |
| Likely pathogenic | |||||||
| T19988+ (M, 18 yr) | SYNGAP1 | Lys108Valfs*25 | EE | Unk (in foster care) FDS | MFD, DS | Unk | Moderate ID ASD (unk) |
| T15924# (M, 11 yr) | SYNGAP1 | Unk (c.389-2A>T) | EE | Ab (6mth) TC | GSW, GPSW, MFD | Delayed | Severe ID, ASD (yes) |
| T22387+ (F, 7 yr) | SYNGAP1 | Arg143* | EE | Ab(10mth) MJ | GSW | Delayed | Severe ID, ASD (yes) |
| T162# (M, 33 yrs) | HNRNPU | Tyr805* | LGS | At (2 y) aAb, MJ, NCS, T, TC | GSW, GPSW, DS, SSW, GPFA | Delayed | Severe ID (yes) |
Polyphen and SIFT scores given for missense variants only.
Initial seizure listed first (age of onset, mth – months, y - years), subsequent seizure types. M- male F-female.
Parents unavailable,
father unavailable.
Accession numbers: CHD2, NM_001271.3, NP_001262.3; SYNGAP1, NM_006772.2, NP_006763.2; MBD5, NM_018328.4, NP_060798.2; GABRG2, NM_000816.3, NP_000807.2; MEF2C, NM_002397.4, NP_002388.2; HNRNPU, NM_031844.2, NP_114032.2.
EE = Epileptic encephalopathy; LGS = Lennox Gastaut syndrome; MAE = Myoclonic atonic epilepsy. aAb = atypical absence; Ab = absence; At = atonic; FDS = focal dyscognitive seizures; FS = febrile seizures; H = hemiclonic; IS = infantile spasms; MJ = myoclonic jerks; NCS = non-convulsive status epilepticus; SE = status epilepticus; T = tonic; TC = tonic-clonic; DS = Diffuse Slowing; ED = epileptiform discharge; GPFA = Generalised Paroxysmal Fast Activity; GPSW = Generalised Polyspike Wave; GSW = Generalised Spike Wave; Hz = Hertz; MFD = Multi-Focal Discharges; PPR = Photoparoxysmal Response