Table 3.
Pathogenic and likely pathogenic mutations adhered to ACMG guidelines in 172 refractory epilepsy children
| Case code | Gene | Gene location | Transcript | cDNA change | Protein change | SIFT | PP2 | MT | HSF | GERP++ | MAF-ExAC | MAF-KG | Parental Origin | ACMG scoring | ACMG pathogenicity | Diagosis |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 13 | SCN1A | chr2–166,901,702 | NM_006920 | c.1513A > T | p.K505X | – | – | A | – | 6.17 (C) | – | – | De novo | PVS1 + PS2 + PM2 | LP | DS |
| 23 | SCN1A | chr2–166,854,657 166,854,660 a [101] | NM_006920 | c.4331_4334del | p.E1444fs | – | – | – | – | – | – | – | De novo | PVS1 + PS1 + PS2 + PM2 | P | DS |
| 26 | SCN1A | chr2–166,870,270 | NM_001165963 | c.3689T>C | p.L1230P | D | D | D | – | 5.28 (C) | – | – | De novo | PS2 + PM1 + PM2 + PP3 | LP | DS |
| 35 | SCN1A | chr2–166,900,287 166,900,288 | NM_001165963 | c.1934_1935del | p.V645fs | – | – | – | – | – | – | – | De novo | PVS1 + PS2 + PM2 | P | DS |
| 38 | SCN1A | chr2–166,859,121 | NM_006920 | c.G4112T | p.G1371V | D | P | D | – | 5.54 (C) | – | – | De novo | PS2 + PM2 | LP | DS |
| 53 | SCN1A | chr2–166,894,306 166,894,337 | NM_001165963 | c.2895_2926del | p.Q965fs | – | – | – | – | – | – | – | Unknown | PVS1 + PM2 | LP | DS |
| 56 | SCN1A | chr2–166,908,355 a [102] | NM_006920 | c.838T > C | p.W280R | D | D | D | – | 5.41 (C) | – | – | De novo | PS1 + PS2 + PM2 + PP3 | P | DS |
| 65 | SCN1A | chr2–166,850,927 | NM_006920 | c.4549-1G > C | splicing | – | – | D | + | 5.76 (C) | – | – | De novo | PVS1 + PS2 + PM2 | P | DS |
| 115 | SCN1A | chr2–166,848,614 | NM_006920 | c.5138C > A | p.A1713D | D | D | D | – | 5.8 (C) | – | – | De novo | PS2 + PM2 + PP3 | LP | DS |
| 124 | SCN1A | chr2–166,848,438 a [103] | NM_006920 | c.5314G > A | p.A1772T | D | D | D | – | 5.69 (C) | – | – | De novo | PS1 + PS2 + PM2 + PP3 | P | DS |
| 130 | SCN1A | chr2–166,854,634 166,854,639 a [101] | NM_006920 | c.4352_4356del | p.Y1451Cfs*22 | – | – | – | – | – | – | – | De novo | PVS1 + PS1 + PS2 + PM2 | P | DS |
| 140 | SCN1A | chr2–166,911,210 166,911,211 | NM_006920 | c.539delT | p.L180X | – | – | – | – | – | – | – | De novo | PVS1 + PS2 + PM2 | P | DS |
| 148 | SCN1A | chr2–166,901,579 | NM_001165963 | c.1636G > T | p.E546X | – | – | A | – | 6.17 (C) | – | – | Unknown | PVS1 + PM2 | LP | DS |
| 149 | SCN1A | chr2–166,894,430 a [104] | NM_006920 | c.2769G > A | p.M923I | D | D | D | – | 5.18 (C) | – | – | Paternal | PS1 + PM2 + PP3 | LP | DS |
| 162 | SCN1A | chr2–166,848,043 166,848,045 | NM_001165963 | c.5740_5742del | p.1914_1914del | – | – | – | – | – | – | – | De novo | PS2 + PM2 + PM4 | LP | DS |
| 172 | SCN1A | chr2–166,903,330 | NM_006920 | c.1327G > T | p.E443X | – | – | A | – | 5.31 (C) | – | – | De novo | PVS1 + PS2 + PM2 | P | DS |
| 93 | SCN2A | chr2–166,243,416 | NM_001040142 | c.4712T > C | p.I1571T | D | D | D | – | 5.17 (C) | – | – | De novo | PS2 + PM1 + PM2 + PP3 | LP | OS |
| 55 | KCNQ2 | chr20–62,073,781 a [105] | NM_172107 | c.794C > T | p.A265V | D | P | D | – | 3.38 (C) | – | – | De novo | PS1 + PS2 + PM2 | P | OS |
| 90 | STXBP1 | chr9–130,423,419 a [53] | NM_003165 | c.364C > T | p.R122X | – | – | A | – | 4.92 (C) | – | – | Unknown | PVS1 + PS1 + PM2 | P | OS-WS |
| 52 | ADSL | chr22–40,745,935 | NM_000026 | c.253C > T | p.R85X | – | – | A | – | 5.59 (C) | – | – | Maternal | PVS1 + PM2 | LP | WS |
| chr22–40,742,633 [58] | NM_000026 | c.71C > T | p.P24L | T | B | D | – | 0.153 (N) | – | – | Paternal | PM2 | UC | |||
| 89 | KCNT1 | chr9–138,651,532 a [106] | NM_020822 | c.862G > A | p.G288S | T | D | D | – | 5.05 (C) | – | – | De novo | PS1 + PS2 + PM1 + PM2 | P | WS |
| 104 | CDKL5 | chrX-18,593,592 18,593,593 | NM_003159 | c.265delT | p.F89Lfs*24 | – | – | – | – | – | – | – | De novo | PVS1 + PS2 + PM2 | P | WS |
| 151 | STXBP1 | chr9–130,428,529 | NM_003165 | c.748C > T | p.Q250X | – | – | A | – | 5.72 (C) | – | – | De novo | PVS1 + PS2 + PM2 | P | WS |
| 29 | SYNGAP1 | chr6–33,393,659 33,393,662 | NM_006772 | c.274_277del | p.G92fs | – | – | – | – | – | – | – | De novo | PVS1 + PS2 + PM2 | P | Doose |
| 164 | SLC2A1 | chr1–43,396,517 | NM_006516 | c.296T > G | p.M99R | D | B | D | – | 5.51 (C) | – | – | De novo | PS2 + PM2 | LP | GLUT1-DS |
| 30 | MECP2 | chrX-153,296,516 a [63] | NM_001110792 | c.799C > T | p.R267X | – | – | A | – | 3.55 (C) | – | – | De novo | PVS1 + PS1 + PS2 + PM2 | P | Rett |
| 32 | TSC2 | chr16–2,126,095 a [91] | NM_000548 | c.2666C > T | p.A889V | D | D | D | – | 5.09 (C) | – | – | Paternal | PS1 + PM2 + PP3 | LP | TSC |
| 94 | TSC2 | chr16–2,130,180 a [107] | NM_000548 | c.3412C > T | p.R1138X | – | – | A | – | 4.74 (C) | – | – | De novo | PVS1 + PS1 + PS2 + PM2 | P | TSC |
| TSC2 | chr16–2,130,366 a [66] | NM_000548 | c.3598C > T | p.R1200W | D | D | D | – | 4.74 (C) | – | – | De novo | PS1 + PS2 + PM2 + PP3 | P | ||
| 98 | TSC2 | chr16–2,138,467 | NM_001077183 | c.5079C > G | p.Y1693X | – | – | D | – | 0.137 (N) | – | – | Paternal | PVS1 + PM2 | LP | TSC |
| TSC2 | chr16–2,138,465 2,138,466 | NM_001077183 | c.5077delT | p.Y1693fs | – | – | – | – | – | – | – | Paternal | PVS1 + PM2 | LP | ||
| 7 | SCN8A | chr12–52,184,209 a [108] | NM_001177984 | c.4324G > A | p.E1442K | D | D | D | – | 4.68 (C) | – | – | Paternal | PS1 + PM2 + PP3 | LP | UEE |
| IQSEC2 | chrX-53,263,621 53,263,622 | NM_001111125 | c.4246_4247insG | p.S1416fs | – | – | – | – | – | – | – | De novo | PVS1 + PS2 + PM2 | P | ||
| 63 | CACNA1A | chr19–13,566,019 a [109] | NM_001127221 | c.301G > C | p.E101Q | D | D | D | – | 5.01 (C) | – | – | De novo | PS1 + PS2 + PM1 + PM2 + PP3 | P | UEE |
| 66 | SCN8A | chr12–52,200,885 a [110] | NM_001177984 | c.5492G > A | p.R1831Q | D | D | D | – | 4.91 (C) | – | – | De novo | PS1 + PS2 + PM2 + PP3 | P | UEE |
| 69 | PCDH19 | chrX-99,551,873 99,551,874 | NM_001184880 | c.2849-1G > − | splicing | – | – | – | + | – | – | – | Unknown | PVS1 + PM2 | LP | UEE |
| 157 | GABRB3 | chr15–26,812,802 a [111] | NM_021912 | c.761C > T | p.S254F | D | D | D | – | 6.06 (C) | – | – | De novo | PS1 + PS2 + PM1 + PM2 + PP3 | P | UEE |
| 160 | GABRA1 | chr5–161,309,645 a [112] | NM_001127648 | c.641G > A | p.R214H | D | D | D | – | 5.34 (C) | – | – | De novo | PS1 + PS2 + PM1 + PM2 + PP3 | P | UEE |
| 54 | CHD2 | chr15–93,540,231 | NM_001271 | c.3640G > T | p.G1214X | – | – | A | – | 5.64 (C) | – | – | De novo | PVS1 + PS2 + PM2 | P | UEE |
| 40 | VRK2 | chr2–58,312,086 | NM_001130483 | c.C256 + 1G > A | splicing | – | – | D | + | 5.86 (C) | – | – | Unknown | PVS1 + PM2 | LP | UE |
| 44 | ATP1A2 | chr1–160,098,521 | NM_000702 | c.1097G > T | p.G366V | D | D | D | – | 4.77 (C) | – | – | De novo | PS2 + PM1 + PM2 + PP3 | LP | UE |
| 68 | TSC1 | chr9–135,772,854 | NM_000368 | c.2768_2769insC | p.L924Ffs*26 | – | – | – | – | – | – | – | De novo | PVS1 + PS2 + PM2 | P | UE |
| 79 | SLC9A6 | chrX-135,080,322 135,080,336 | NM_001042537 | c.582_595del | p.Y194fs | – | – | – | – | – | – | – | De novo | PVS1 + PS2 + PM2 | P | UE |
Abbreviations: M male, F female, m month, y year, SIFT Sorts intolerant from tolerant (D, damaging; T, tolerant), PP2, polymorphism phenotyping v2 (D, damaging; P, possible damaging; B, benign), MT mutation taster (D, disease causing; A, disease causing automatic), HSF human splicing finder (+, altering splicing), GERP++ genomic evolutionary rate profiling (C, conserved; N, nonconserved), KG 1000 Genomes project, LP likely pathogenic, P pathogenic, DS Dravet syndrome, OS Ohtahara syndrome, OS-WS OS syndrome evolves to West syndrome, WS West syndrome, Doose Doose syndrome, GLUT1-DS glucose transporter type 1 deficiency syndrome, Rett Rett syndrome, TSC tuberous sclerosis complex, UEE unclassified epileptic encephalopathy, UE unclassified refractory epilepsy
a Mutations have been reported in HGMD database