Table 2.
Patients with definite/likely diagnosis and treatment impact.
| ID Sex | AAO | Epilepsy type | Gene (IP) | GRCh37/hg19 | Variant | Zyg | Origin | Treatment Impact |
|---|---|---|---|---|---|---|---|---|
| PROSPECTIVE PATIENTS | ||||||||
| 001 M | 3 m | Dravet | SCN1A (AD) | chr2:166848491 | NM_001165963:c.5294T>C;p.F1765S | het | De novo | Change from levetiracetam to clobazam, valproic acid, and topiramate |
| 010 F | 18.3 m | Unclassified | SMC1A (XLD) | chrX:53409269 | NM_006306:c.3321C>G;p.Y1107X | het | De novo | |
| 018 F | 6 m | Ohtahara, West | STXBP1 (AD) | chr9:130434396 | NM_003165:IVS12+1GT>AA;NAc | het | De novo | |
| 033 F | 9.2 m | EE | POLG (AR) | chr15:89871929 | NM_002693:c.1157G>C;p.R386P | comp het | ♀carrier | Stopped valproic acid; early palliative care; prenatal testing for next pregnancy |
| chr15:89866657 | NM_002693:c.2243G>C;p.W748S | ♂carrier | ||||||
| 059 M | 24 m | Unclassified | GABRA1 (AD) | chr5:161322788 | NM_000806:c.973T>C;p.F325L | het | De novo | |
| 069 M | 51.5 m | Unclassified | MED23 (AR) | chr6:131944505 | NM_015979:c.382G>A;p.G128R | comp het | ♀carrier | |
| chr6:131941826 | NM_015979:c.539C>A;p.A180D | ♂carrier | ||||||
| 098 M | 1.5 m | Unclassified | KCNT1 (AD) | chr9:138660693 | NM_020822:c.1420C>G;p.R474G | het | De novo | No change in management |
| 104 M | 0.9 m | SLFNE | KCNQ2 (AD) | chr20:62059782 | NM_172107:c.154delT;p.I385TfsTer4 | het | ♀carrier | Stopped phenobarbital at 2 m; avoided MRI with anesthetic; seizure free and normal development at 6 m |
| 120 F | 1.8 m | West syndrome | ADSL (AR) | chr22:40754948 | NM_000026:c.563G>A;p.R188H | comp het | ♀carrier | S-Adenosyl-I-methionine trial proposed but patient died just prior to implementation |
| chr22:40760969 | NM_000026:c.1277G>A;p.R426H | ♂carrier | ||||||
| 144 F | 3 days | Unclassified | FGF12a (AD) | chr3:192053223 | NM_021032:c.341G>A;p.R114H | het | De novo | Remains seizure free with normal development on carbamazepine |
| 165 M | 21.6 m | Dravet | SCN1A (AD) | chr2:166915162 | NM_001165963:c.301C>T;p.R101W | het | De novo | Avoiding sodium channel blockers and started Valproic acid early |
| 167 F | 7.7 m | Unclassified | SCN8A (AD) | chr12:52200900 | NM_014191:c.5630A>G;p.N1877S | het | ♂carrier | Kept on Sodium channel blockers. Seizure free and normal development |
| 193 M | 1.5 m | West syndrome | ARX (XLR) | chrX:25022869 | NM_139058:c.1607G>C;p.R536T | hemi | ♀carrier | |
| 197 M | 4.4 m | Dravet | SCN1A (AD) | chr2:166866246 | NM_001165963:c.3985C>T;p.R1329X | het | De novo | Avoiding sodium channel blockers and started Valproic acid early |
| 200 F | 8.9 m | Dravet | SCN1A (AD) | chr2:166859067 | NM_001165963:c.4198delA;p.I1400X | het | Unknown | Avoiding sodium channel blockers and started Valproic acid early |
| 201 M | 4.6 m | Dravet | SCN1A (AD) | chr2:166848872 | NM_001165963:c.4913T>A;p.I1638N | het | De novo | Avoiding sodium channel blockers and started Valproic acid early |
| 205 M | 3 days | EE | SCN1A (AD) | chr2:166848429 | NM_001165963:c.5356C>G;p.L1786V | het | De novo | Influenced medication choice: topiramate |
| 206 M | 4.6 m | Unclassified | PRRT2 (AD) | chr16:29824973 | NM_145239:c.604_607delTCAC;p.S202HfsTer26 | het | ♂carrier | No change in management |
| 222 F | 52.1 m | EE | MECP2 (XLD) | chrX:153296878 | NM_004992:c.401C>G;p.S134C | het | De novo | |
| 234 M | 0.8 w | Unclassified | ALDH7A1 (AR) | chr5:125882034 | NM_001182:c.1547A>G;p.Y516C | het | ♀carrier | Treated with B6, lysine restricted diet |
| chr5:125887751 | NM_001182:c.1279G>C;p.E427Q | het | ♂carrier | |||||
| 237 F | 1 m | SLFIE | SCN2A (AD) | chr2:166231307 | NM_021007:c.4085A>T;p.K1362M | het | ♀carrier | Discontinue medication early because of predicted benign course |
| RETROSPECTIVE PATIENTS | ||||||||
| 002 M | 3.2 m | Dravet-like | ATP1A2 (AR) | chr1:160100072 | NM_000702:c.1642C>T;p.R548C | comp het | ♀carrier | Stopped stiripentol; started flunarizine. No further episodes on flunarizin |
| chr1:160109762 | NM_000702:c.3022C>T;p.R1008W | ♂carrier | ||||||
| 005 F | 7 m | West syndrome | ALG13 (XLD) | chrX:110928268 | NM_001099922:c.320A>G;p.N107S | het | De novo | |
| 006 M | 10.4 m | LGS | GABRB3 (AD) | chr15:27017551 | NM_000814:c.238A>G;p.M80V | het | Not ♀, ♂ NA | |
| 013 F | 5 m | EE | KCNQ5a (AD) | chr6:73821107 | NM_001160133:c.1106C>G;p.P369R | het | De novo | |
| 014 M | 0.5 w | EE | PNPT1b (AR) | chr2:55910954 | NM_033109:c.419C>T;p.P140L | hom | ♀ & ♂ carrier | |
| 023 M | 11.2 m | EE | PIGA (XLR) | chrX:15344061 | NM_002641:c.823C>T;p.R275T | hemi | ♀carrier | |
| 039 M | 1 day | EE | KCNQ2 (AD) | chr20:62070997 | NM_172107:c.881C>T;p.A294V | het | De novo | Topiramate changed to carbamazepine: no improvement in seizure frequency 6 months later |
| 040 F | 3 days | EE | KCNQ2 (AD) | chr20:62071034 | NM_172107:c.844G>T;p.D282Y | het | De novo | Phenytoin changed to carbamazepine: seizures less frequent and shorter 9 months later |
| 043 F | 3 m | West syndrome | PAFAH1B1 (AD) | chr17:2577530 | NM_000430:c.849_853delCTGGG;p.W292SfsTer10 | het | De novo | |
| 044 M | 2.1 m | EE | SLC1A2b (AD) | chr11:35336636 | NM_004171:c.244G>A;p.G82R | het | De novo | |
| 050 M | 13.7 m | Unclassified | TUBB2B (AD) | chr6:3226887 | NM_178012:c.74G>A;p.S25N | het | De novo | |
| 063 M | 18.5 m | Unclassified | RORAb (AD) | chr15:60803740 | NM_134261:c.505C>T;p.Q169X | het | De novo | |
| 065 F | 3.5 m | West syndrome | SLC35A2 (AD) | chr20:62070997 | NM_001282651:c.550_552delTCC;p.S184del | het | De novo | Galactose trial: 6 months later more alert and interactive; no change in seizure frequency |
| 071 F | 46.5 m | Unclassified | HNRNPH2b (XLD) | chrX:100667593 | NM_01959:c.617G>A;p.R206Q | het | Not ♀, ♂ NA | |
| 072 M | 29.2 m | Unclassified | TCF20b (AD) | chr22:42611134 | NM_181492:c.178C>T;p.R60X | het | De novo | |
| 073 F | 12 m | EE | YWHAGb (AD) | chr7:75959244 | NM_012479:c.394C>T;p.R132C | het | De novo | |
| 077 F | 2.1 m | West, LGS | CDKL5 (XLD) | chrX:18622288 | NM_003159:c.1245_1246delAG;p.E416VfsTer2 | het | De novo | |
| 093 F | 21.4 m | EE | SMARCA2a (AD) | chr9:2081857 | NM_139045:c.2210C>A;p.S737Y | het | De novo | |
| 094 F | 7 m | Dravet | SCN1A (AD) | chr2:166915157 | NM_001165963:c.305delT;p.F102SfsTer10 | het | De novo | Changed medications: added clobazam and stiripentol |
| 100 F | 10.1 m | Unclassified | ATP1A3 (AD) | chr19:42471896 | NM_152296:c.2839G>A;p.G947R | het | De novo | No change in management. Already on Flunarizine |
| 106 F | 3.7 m | EE | STXBP1 (AD) | chr9:130413885 | NM_003165:c.41T>G;p.I14S | het | De novo | |
| 113 F | 7.5 m | West syndrome | DYNC1H1 (AD) | chr14:102469031 | NM_001376:c.4700G>A;p.R1567Q | het | De novo | |
| 123 F | 11.8 m | EE | GABRA1 (AD) | chr5:161309644 | NM_000806:c.604C>T;p.R214C | het | De novo | Based on functional studies, will be started on new medication (pending publication) |
| 126 F | 60 m | Unclassified | RORAb (AD) | chr15:60803459 | NM_134261:c.785dupG;p.E263RfsTer20 | Het | De novo | |
| 130 F | 1.1 m | West syndrome | DEPDC5 (AD) | chr22:32239187 | NM_001242896:c.2623delT;p.Y875Tfs46 | het | De novo | |
| 132 M | 28.1 m | CSWS | CNKSR2 (XLR) | chrX:21609267 | NM_014927:c.1785G>A;p.W595X | hemi | ♀carrier | |
| 137 F | 24 m | Unclassified | DYRK1A (AD) | chr21:38865409 | NM_001396:c.1042G>A;p.G348R | het | Not ♂, ♀ NA | |
| 138 F | 18 m | EE | DCX (XLD) | chrX:110653428 | NM_178151:c.199G>A;p.G67R | het | De novo | |
| 148 F | 12 m | Unclassified | DYRK1A (AD) | chr21:38865409 | NM_001396:c.763C>T;p.R255X | het | De novo | |
| 152 F | 7 m | EE | NEXMIFb (XLD) | chrX:73962510 | NM_001008537:c.1882C>T;p.R628X | het | unknown | |
| 158 F | 26.4 m | MAE/Febrile seizures plus | SCN1A (AD) | chr2:166848429 | NM_001165963:c.298T>G.F100V | het | De novo | No change in management |
| 160 F | 27.5 m | EE | MECP2 (XLD) | chrX:153296777 | NM_004992:c.502C>T;p.R168X | het | De novo | |
| 168 F | 41.5 m | EE | MECP2 (XLD) | chrX:153296857 | NM_004992:c.422A>C;p.Y141S | het | De novo | |
| 171 F | 10 m | EE | HNRNPU (AD) | chr1:245025823 | NM_031844:c.817C>T;p.Q273X | het | De novo | |
| 208 F | 10.8 m | Unclassified | PCDH19 (XLD) | chrX:99662976 | NM_001184880:c.619_620delCGinsA;p.R207KfsTer5 | het | De novo | Trial of steroids, but no response |
| 213 M | 1 day | Unclassified | ATP1A3 (AD) | chr19:42471896 | NM_152296:c.2443G>A;p.E815K | het | De novo | Started Flunarizine with reduced hemiplegic episodes |
| 230 F | 3.5 m | West, LGS | SCN8A (AD) | chr12:52099304 | NM_014191:c.1238C>A;p.A413D | het | De novo | Sodium channel blocker tried, not continued |
| 248 F | 37 m | Unclassified | SCN1A (AD) | chr2:166909410 | NM_001165963:c.646A>T;p.R216X | het | De novo | Influenced choice of future treatment (stiripentol, CBD oil) |
a
Variants identified by trio WES.
b
Variants identified by WES reanalysis.
AAO, Age At Onset; AD, autosomal dominant; AR, autosomal recessive; CSWS, Epileptic Encephalopathy with continuous spike-and-wave during sleep; D, days; EE, unspecified Epileptic Encephalopathy; FS, Febrile seizure; IP, inheritance pattern; LGS, Lennox-Gastaut syndrome; MAE, Epilepsy with myoclonic-atonic seizures; M, months; NA, not available; SE, status epilepticus; SLFNE, Self-limited familial neonatal/infantile epilepsy; XL, X-linked; Zyg, zygosity; het; heterozygous; hom, homozygous; hemi, hemizygous.
c
c.1029+1_1029+2delGTinsAA disrupts the canonical splice donor site of exon 12 and is predicted to abolish normal splicing.
Patients highlighted in bold are those for whom a genetic diagnosis had treatment implications.