TABLE 1.
Genotypic description of the children with genetic IESS due to monogenic causes.
| Serial no. | Gene | Exon/intron location | Chromosomal location | Type of variation | Specify gene variation | Variant amino acid change | Zygosity | Inheritance pattern | Variant classification as per ACMG | Novelty |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | ALDH7A1 | Exon 12 | Chromosome 5 | Nonsense | c.1048C>T | p.Arg350Ter | Homozygous | AR | Pathogenic | rs1015686016 |
| 2 | ALDH7A1 | Intron 12 and Exon 11 | Chromosome 5 | Splice site and nonsense | c.1093+1G>A and c.1003C>T | 5′ splice site and p.Arg335Ter | Compound heterozygous | AR | Pathogenic | rs794727058; rs1015686016 |
| 3 | ALDH7A1 (ENST00000636879.1) | Exon 16 and Exon 15 | Chromosome 5 | Insertion and nonsense | c.1456_1457insG and c.1269T>G | p.Leu486ArgfsTer4; p.Tyr423Ter | Compound heterozygous | AR | Pathogenic | rs772766995, rs121912710 |
| 4 | ALDH7A1 | Exon 14 | Chromosome 5 | Missense | c.1279G>C | p.Glu427Gln | Homozygous | AR | Pathogenic | rs121912707 |
| 5 | ALDH7A1 | Exon 1 | Chromosome 5 | Nonsense | c.187G>T | p.Gly63Ter | Homozygous | AR | Pathogenic | rs760636660 |
| 6 | ALDH7A1 | Exon 17 | Chromosome 5 | Missense | c.1556G>A | p.Arg519Lys | Homozygous | AR | Likely pathogenic | rs561343926 |
| 7 | ALDH7A1 (ENST00000636879.1) | Exon 7 | Chromosome 5 | Missense | c.575C>A | p.Ala192Glu | Homozygous | AR | Likely pathogenic | rs764417585 |
| 8 | ALDH7A1 | Exon 9 | Chromosome 5 | Nonsense | c.841C>T | p.Gln281Ter | Homozygous | AR | Pathogenic | rs1170817007 |
| 9 | ALDH7A1 | Exon 1 | Chromosome 5 | Nonsense | c.187G>T | p.Gly63Ter | Homozygous | AR | Pathogenic | rs760636660 |
| 10 | ALDH7A1 | Exon 1 | Chromosome 5 | Nonsense | c.187G>T | p.Gly63Ter | Homozygous | AR | Pathogenic | rs760636660 |
| 11 | SCN2A (NM_001040142.2) | Exon 23 | Chromosome 2 | Insertion | c.4004_4005insGGAAT | p.Ser1336GlufsTer5 | Heterozygous | AD | Pathogenic | Novel |
| 12 | SCN2A | Exon 7 | Chromosome 2 | Missense | c.788C>T | p.Ala263Val | Heterozygous | AD | Pathogenic | rs387906686 |
| 13 | SCN2A | Exon 3 | Chromosome 2 | Nonsense | c.330C>A | p.Tyr110Ter | Heterozygous | AD | Pathogenic | Reported without RS id |
| 14 | SCN2A | Exon 27 | Chromosome 2 | Missense | c.5645G>A | p.Arg1882Gln | Heterozygous | AD | Pathogenic | rs794727444 |
| 15 | SCN2A | Exon 23 | Chromosome 2 | Nonsense | c.4303C>T | p.Arg1435Ter | Heterozygous | AD | Pathogenic | rs796053138 |
| 16 | SCN2A | Exon 19 | Chromosome 2 | Missense | c.3631G>A | p.Glu1211Lys | Heterozygous | AD | Pathogenic | rs387906684 |
| 17 | SCN2A | Exon 17 | Chromosome 2 | Missense | c.2995G>A | p.Glu999Lys | Heterozygous | AD | Likely pathogenic | rs796053126 |
| 18 | CDKL5 | Exon 6 | Chromosome X | Missense | c.211A>G | p.Asn71Asp | Heterozygous | XL | Pathogenic | rs587783072 |
| 19 | CDKL5 | Exon 10 | Chromosome X | Missense | c.587C>T | p.Ser196Leu | Heterozygous | XL | Pathogenic | rs267608501 |
| 20 | CDKL5 | Exon 6 | Chromosome X | Missense | c.248G>T | p.Gly83Val | Heterozygous | XL | Pathogenic | rs587783402 |
| 21 | CDKL5 (NM_001323289.2) | Exon 18 | Chromosome X | Deletion | c.2486delT | p.Leu829Argfs*8 | Heterozygous | XL | Pathogenic | Novel |
| 22 | CDKL5 | Intron 9 | Chromosome X | Splice site | c.554+5G>A | 5′ Splice site | Heterozygous | XL | Pathogenic | rs1925577525 |
| 23 | CDKL5 (ENST000 00379989) | Exon 10 | Chromosome X | Deletion | c.633delT | p.Pro212LeufsTer16 | Heterozygous | XL | Pathogenic | Novel |
| 24 | ALG13 | Exon 3 | Chromosome X | Missense | c.320A>G | p.Asn107Ser | Hemizygous | XL | Pathogenic | rs398122394 |
| 25 | ALG13 | EXON ‐3 | Chromosome X | Missense | c.320A>G | p.Asn107Ser | Hemizygous | XL | Pathogenic | rs398122394 |
| 26 | ALG13 | Exon 17 | Chromosome X | Missense | c.2057G>A | p.Cys686Tyr | Hemizygous | XL | Likely pathogenic | rs767698446 |
| 27 | ALG13 | Exon 3 | Chromosome X | Missense | c.320A>G | P.Asn107Ser | Hemizygous | XL | Likely pathogenic | rs398122394 |
| 28 a | ALG13 | Exon 3 | Chromosome X | Missense | c.320A>G | p.Asn107Ser | Hemizygous | XL | Likely pathogenic | rs398122394 |
| 29 | KCNQ2 | Exon 5 | Chromosome 20 | Missense | c.793G>A | p.Ala265Thr | Heterozygous | AD | Pathogenic | rs794727740 |
| 30 | KCNQ2 | Exon 6 | Chromosome 20 | Missense | c.917C>T | p.Ala306Val | Heterozygous | AD | Pathogenic | rs864321707 |
| 31 | KCNQ2 (NM_172107.4) | Exon 6 | Chromosome 20 | Missense | c.850T>C | p.Tyr284His | Heterozygous | AD | Likely pathogenic | Reported without RS id |
| 32 | KCNQ2 | Exon 5 | Chromosome 20 | Missense | c.794C>T | p.Ala265Val | Heterozygous | AD | Likely pathogenic | rs587777219 |
| 33 | STXBP1 | Exon 18 | Chromosome 9 | Missense | c.1654T>C | p.Cys552Arg | Heterozygous | AD | Pathogenic | rs1842046459 |
| 34 | STXBP1 | Exon 9 | Chromosome 9 | Missense | c.704G>A | p.Arg235Gln | Heterozygous | AD | Pathogenic | rs794727970 |
| 35 | STXBP1 | Exon 14 | Chromosome 9 | Missense | c.1216C>T | p.Arg406Cys | Heterozygous | AD | Pathogenic | rs796053367 |
| 36 | STXBP1 (ENST00000637953.1) | Exon 10 | Chromosome 9 | Nonsense | c.863G>A | p.Trp288Ter | Heterozygous | AD | Pathogenic | Novel |
| 37 | WWOX (ENST00000566780.6) | Exons 6 and 9 | Chromosome 16 | Deletion and missense | c.553_566del and c.1193G>A | p.Ala185ArgfsTer6 and p.Trp398Ter | Compound heterozygous | AR | Likely pathogenic | rs759794876; Novel |
| 38 | WWOX (ENST00000566780.6) | Exons 2 and 7 | Chromosome 16 | Deletion and nonsense | c.155_156del and c.744C>A | p.Arg52Lyster16 and p.cys248Ter | Compound heterozygous | AR | Pathogenic | Novel; Novel |
| 39 | WWOX (ENST00000566780.6) | Exons 5 to 8; Intron 5 | Chromosome 16 | Deletion; splice site | (516+1_517–1)_(1056+1_1057‐1)del; c.517‐3c>A | Exonic deletion and 3′ splice site | Compound heterozygous | AR | Likely pathogenic | Uncertain; Novel |
| 40 | WWOX | Exon 7 | Chromosome 16 | Nonsense | c.790C>T | p.Arg264Ter | Homozygous | AR | Pathogenic | rs756762196 |
| 41 | SCN1A | Exon 16 | Chromosome 2 | Missense | c.2311G>A | p.Asp771Asn | Heterozygous | AD | Likely pathogenic | Reported without RS id |
| 42 | SCN1A | Intron 28 | Chromosome 2 | Splice site | c.4853‐1G>C | 3′ splice site | Heterozygous | AD | Pathogenic | rs1553520530 |
| 43 a | SCN1A (ENST00000674923.1) | Exon 15 | Chromosome 2 | Duplication | c.2712dupT | p.Ala905CysfsTer10 | Heterozygous | AD | Likely pathogenic | Novel |
| 44 | SCN1A | Exon 7 | Chromosome 2 | Missense | c.1007G>A | p.Cys336Tyr | Heterozygous | AD | Likely pathogenic | rs794726798 |
| 45 | NTRK2 (NM_006180.6) hg19 | Exon 12 | Chromosome 9 | Missense | c.1301A>G | p.Tyr434Cys | Heterozygous | AD | Likely pathogenic | rs886041091 |
| 46 a | NTRK2 (NM_006180.6) hg19 | Exon 12 | Chromosome 9 | Missense | c.1301A>G | p.TyrY434Cys | Heterozygous | AD | Likely pathogenic | rs886041091 |
| 47 a | NTRK2 (NM_006180.6) hg19 | Exon 12 | Chromosome 9 | Missense | c.1301A>G | p.Tyr434Cys | Heterozygous | AD | Likely pathogenic | rs886041091 |
| 48 a | NTRK2 (NM_006180.6) hg19 | Exon 12 | Chromosome 9 | Missense | c.1301A>G | p.Tyr434Cys | Heterozygous | AD | Likely pathogenic | rs886041091 |
| 49 | KCNT1 (ENST00000371757.7) | Intron 2 | Chromosome 9 | 3′ splice site | c.255‐2A>G | 3′ splice site | Heterozygous | AD | Pathogenic | Novel |
| 50 | KCNT1 | Exon 12 | Chromosome 9 | Missense | c.1038C>G | p.Phe346Leu | Heterozygous | AD | Pathogenic | rs767434859 |
| 51 | KCNT1 | Exon 11 | Chromosome 9 | Missense | c.862G>A | p.Gly288Ser | Heterozygous | AD | Pathogenic | rs587777264 |
| 52 | SYNGAP1 | Exon 5 | Chromosome 6 | Nonsense | c.490C>T | p.Arg164Ter | Heterozygous | AD | Pathogenic | rs1057518352 |
| 53 | SYNGAP1 | Exon 8 | Chromosome 6 | Non‐sense | c.1081C>T | p.Gln361Ter | Heterozygous | AD | Pathogenic | rs1554121231 |
| 54 | SYNGAP1 | Exon 17 | Chromosome 6 | Non‐sense | c.3718C>T | p.Arg1240Ter | Heterozygous | AD | Pathogenic | rs869312955 |
| 55 | SCN3A | Exon 28 | Chromosome 2 | Missense | c.5576G>A | p.Arg1859His | Heterozygous | AD | Likely pathogenic | rs778995406 |
| 56 | SCN3A | Exon 28 | Chromosome 2 | Missense | c.5576G>A | p.Arg1859His | Heterozygous | AD | Likely pathogenic | rs778995406 |
| 57 | SCN3A (NM_006922.4) | Exon 21 | Chromosome 2 | Missense | c.3734A>C | p.Lys1245Thr | Heterozygous | AD | Likely pathogenic | Reported without RS id |
| 58 | SLC2A1 (NM_006516.4) | Exon 9 | Chromosome 1 | Duplication | c.1119dup | p.Gly374TrpfsTer7 | Heterozygous | AD | Pathogenic | Novel |
| 59 | SLC2A1 (NM_006516.4) | Exon 6 | Chromosome 1 | Missense | c.691C>G | p.Leu231Val | Homozygous | AR | Pathogenic | Novel |
| 60 | SLC2A1 (NM_006516.4) | Exon 6 | Chromosome 1 | Missense | c.691C>G | p.Leu231Val | Homozygous | AR | Pathogenic | Novel |
| 61 | MECP2 | Exon 2 | Chromosome X | Deletion | ChrX:g.(?_154019188_(154031459_?)del | Exonic deletion of 12.27 kb | Heterozygous | XL | Pathogenic | – |
| 62 | MECP2 | Exon 3 | Chromosome X | Nonsense | c.799C>T | p.Arg267Ter | Heterozygous | XL | Pathogenic | rs61749721 |
| 63 | CPLX1 (ENST00000304062.11) | Exon 3 | Chromosome 4 | Deletion | c.151_183del | p.Lys51_Ala61del | Homozygous | AR | Pathogenic | Novel |
| 64 | CPLX1 (ENST00000304062.11) | Exon 4 | Chromosome 4 | Nonsense | c.210C>G | p.Tyr70Ter | Homozygous | AR | Likely pathogenic | Reported without RS id |
| 65 | UGP2 (ENST00000445915.6) | Exon 2 | Chromosome 2 | Missense | c.61A>G | p.Met21Val | Homozygous | AR | Likely pathogenic | rs768305634 |
| 66 | UGP2 | Exon 2 | Chromosome 2 | Missense | c.34A>G | p.Met12Val | Heterozygous | AR | Likely pathogenic | rs768305634 |
| 67 | PPP3CA (NM_000944.5) | Exon 12 | Chromosome 4 | Deletion | c.1255_1256del | p.Ser419CysfsTer31 | Heterozygous | AD | Pathogenic | rs1553920383 |
| 68 | PPP3CA | Exon 12 | Chromosome 4 | Duplication | c.1283dup | p.Thr429AsnfsTer22 | Heterozygous | AD | Pathogenic | rs1727004803 |
| 69 | GRM7 | Exons 3–4 | Chromosome 3 | Deletion | c.(736+1_737–1)_(1033+1_1034‐1)del | Exonic deletion of 7.99 kb | Homozygous | AR | Likely pathogenic | – |
| 70 | TBCD | Exon 18 | Chromosome 17 | Missense | c.1661C>T | p.Ala554Val | Homozygous | AR | Likely pathogenic | rs1555641324 |
| 71 | CHD2 | Exon 37 | Chromosome 15 | Missense | c.4763G>A | p.Arg1588Gln | Heterozygous | AD | Likely pathogenic | rs1164926261 |
| 72 | CDK19 (NM_015076.5) | Exon 12 | Chromosome 6 | 18 base pair duplication | c.1113_1130dup | p.Gln373_Gln378dup | Heterozygous | AD | Likely pathogenic | Novel |
| 73 | FOXG1 (NM_005249.5) | Exon 1 | Chromosome 14 | Single BP insertion | c.953_954insC | p.Arg320ProfsTer135 | Heterozygous | AD | Pathogenic | Novel |
| 74 a | NRROS | Exon 2 | Chromosome 3 | Deletion | c.1359del | p.Ser454Alafs*11 | Homozygous | AR | Likely pathogenic | rs1346764478 |
| 75 a | PURA (NM_005859.5) | Exon 1 | Chromosome 5 | Duplication | c.479dup | p.Glu161GlyfsTer40 | Heterozygous | AD | Pathogenic | Novel |
| 76 | KANSL1 | Exon 6 | Chromosome 17 | Missense | c.1799A>G | p.Lys600Arg | Heterozygous | AD | Likely pathogenic | rs770594188 |
| 77 | GABBR2 (NM_005458.8) | Exon 15 | Chromosome 9 | Missense | c.2084G>A | p.Ser695Asn | Heterozygous | AD | Likely pathogenic | Reported without RS id |
| 78 | GRIN1 | Exon 18 | Chromosome 9 | Missense | c.2452A>C | p.Met818Leu | Heterozygous | AD | Likely pathogenic | rs1554770628 |
| 79 | CSNK2A1 (NM_001895.4) | Exon 13 | Chromosome 20 | Missense | c.1012A>G | p.Ser338Gly | Heterozygous | AD | Likely pathogenic | Novel |
| 80 | PNPO | EXON 4 | Chromosome 17 | Missense | c.413G>A | p.Arg138His | Homozygous | AR | Likely pathogenic | rs764940495 |
| 81 | CACNA1A (NM_001127222.2) | Exon 20 | Chromosome 19 | Deletion | c.3550delC | p.His1180ThrfsTer6 | Heterozygous | AD | Likely pathogenic | Novel |
| 82 | PLPBP (NM_007198.4) | Exon 8 | Chromosome 8 | Missense | c.727G>A | p.Gly243Arg | Homozygous | AR | Likely pathogenic | Novel |
| 83 | NPRL3 | Exon 5 | Chromosome 16 | Deletion | c.423_426del | p.Leu142IlefsTer27 | Heterozygous | AD | Pathogenic | rs1567139896 |
| 84 | PLPBP (NM_007198.4) | Exon 8 | Chromosome 8 | Missense | c.727G>A | p.Gly243Arg | Homozygous | AR | Likely pathogenic | Novel |
| 85 | IQSEC2 (ENST000 00396435. 3) | Exon 7 | Chromosome X | Nonsense | chrX:g.53277315G>A | p.Arg855Ter | Homozygous | XL | Pathogenic | rs587777261 |
| 86 | CYFIP2 | Exon 4 | Chromosome 5 | Missense | c.259C>T | p.Arg87Cys | Heterozygous | AD | Likely pathogenic | rs1131692231 |
| 87 | MBOAT7 (NM_024298.5) | Exon 8 | Chromosome 19 | Deletion | c.1059del | p.Tyr354ThrfsTer11 | Homozygous | AR | Likely pathogenic | Novel |
| 88 | MBD5 | Exon 8 | Chromosome 2 | Insertion | c.539_540ins | p.Gln190TyrfsTer88 | Heterozygous | AD | Pathogenic | – |
| 89 | PPP2R1A (NM_014225.6) | Intron 10 | Chromosome 19 | Splice site | c.1302+2T>G | 5′ splice site | Heterozygous | AD | Pathogenic | Novel |
| 90 | DNM1 | Exon 6 | Chromosome 9 | Missense | c.709C>T | p.Arg237Trp | Heterozygous | AD | Likely pathogenic | rs760270633 |
| 91 | NONO | Intron 8 | Chromosome X | Splice site | c.1028+3A>G | 5′ splice site proximal | Hemizygous | XL | Likely pathogenic | rs1447518463 |
| 92 | EHMT1 | Exon 19 | Chromosome 9 | Missense | c.2842C>T | p.Arg948Trp | Heterozygous | AD | Likely pathogenic | rs368702408 |
| 93 | GNAO1 | Exon 8 | Chromosome 16 | Missense | c.935A>G | p.Asn312Ser | Heterozygous | AD | Pathogenic | rs758503575 |
| 94 | PRRT2 | Exon 2 | Chromosome 16 | Duplication | c.649dupC | p.Arg217Profs*8 | Heterozygous | AD | Pathogenic | rs587778771 |
| 95 | AMT | Exon 7 and Exon 1 | Chromosome 3 | Missense and others | c.794G>A and c.2T>C | p.Arg265His and p.Met1Thr | Compound Heterozygous | AR | Likely pathogenic | rs757918826; rs1266259634 |
| 96 | KMT2C | Intron 37 | Chromosome 7 | 4 (splice acceptor variant) | c.7443‐2delA | Splice acceptor variant | Heterozygous | AD | Likely pathogenic | rs753425356 |
| 97 | ADSL (ENST00000216194) hg19 | Intron 6 and Exon 9 | Chromosome 22 | Missense | c.701+1G>A; and c.926G>A | 5′ splice site and p.Arg309His | Compound Heterozygous | AR | Likely pathogenic | rs546878201; rs749817666 |
| 98 | SATB1 (NM_001131010.4) | Intron 10 | Chromosome 3 | Splice site | c.1780‐2A>G | 3′ splice site | Heterozygous | AD | Pathogenic | Novel |
| 99 | PACS2 (ENST00000447393.6) | Exon 6 | Chromosome 14 | Missense | c.625G>A | p.Glu209Lys | Heterozygous | AD | Likely pathogenic | Novel |
| 100 | HUWE1 | Exon 64 | Chromosome X | Missense | c.9209G>A | p.Arg3070His | Hemizygous | XL | Pathogenic | rs2061745581 |
| 101 | ASNS | Exon 10 | Chromosome 7 | Missense | c.1138G>T | p.Ala380Ser | Homozygous | AR | Likely pathogenic | rs758183057 |
| 102 | MIPEP (NM_005932.4) | Exon 13 | Chromosome 13 | Missense | c.1409T>C | p.Leu470Pro | Homozygous | Ar | Likely pathogenic | Novel |
| 103 | PLEKHG2 | Exons 18 and 19 | Chromosome 19 | Both missense | c.1855G>A and c.3953C>T | p.Glu619Lys and p.Ser1318Leu | Compound Heterozygous | AR | Likely pathogenic | rs750591987; rs755575206 |
| 104 | SCN8A | Exon 27 | Chromosome 12 | Missense | c.5614C>T | p.Arg1872Trp | Heterozygous | AD | Likely pathogenic | rs796053228 |
| 105 | MT‐ND5 | Mitochondrial DNA | Mitochondrial DNA | Missense | m.13513G>A | p.Asp393Asn | Heteroplasmic | Mito | Pathogenic | rs267606897 |
a
Previously published cases.