Table 2. Summary of the 13 Cases with Variants Detected in Our Study.
| Patient | Age of Onset | Clinical Diagnosis | Seizures types | EEG (age) | Neuroimaging | Response to AEDs | DQ/IQ results & Age at evaluation | ID | Mutant Gene, Inheritance | HGMD Reported or Novel | SIFT/Polyphen 2 Prediction | Mutation | Location of Variant (Protein) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Pathogenic Variants | |||||||||||||
| C0106 | 1 month (M) | WS | Partial then epileptic spasms | Hypsarrhythmia | Ventriculomegaly | Resistant to AEDs and ketogenic diet | (30) 2 y and 8 mo | Severe | CDKL5 Xp22.13, de novo | Novel | / | (NM_003159) chrX :18593605–18593606(insA) c.278dupA/p.E93fs | Protein kinase domain |
| S553 | 3 months (F) | WS | Partial then epileptic spasms | Hypsarrhythmia | Normal | Resistant to AEDs and ketogenic diet | (27) 1 y and 5 mo | Severe | CDKL5 Xp22.13, de novo | (Zhao 2014)1 | / | (NM_003159) chrX :18622154–18622155(delC) c.1110delC/p.N370fs | Cytoplasmic domain |
| S559 | 2 days (F) | uEEEs | Tonic | Sharp waves | Arachnoid cyst | PB then lev and VPA (not controlled) then monotherapy LEV (seizure-free) | (60) 4mo & (55) 4 y | Mild | KCNQ2 20q13.33, de novo | (Moulard 2001)2,**** | Deleterious/probably damaging | (NM_004518) chr20:62044908(G > A) c.1574G > A/p.R525Q | C-terminal |
| C0107 | 1 months (F) | uEEEs | Partial | Spikes, slow-spike-and-wave and polyspike-and-wave complexes | Normal | LEV then LEV and VPA (seizures-controlled) | (42) 1 y and 6 mo | Moderate | KCNQ2 20q13.33, NT | (Moulard 2001)2,**** | Deleterious/probably damaging | (NM_004518) chr20:62044908(G > A) c.1574G > A/p.R525Q | C-terminal |
| S557 | 4 months (M) | uEEEs | Tonic | Hypsarrhythmia, Spike wave (11 months) | Ventriculomegaly | LEV then LEVPB and CBZ, then VPA (refractory seizures) | (36) 2 y | Moderate | SCN8A 12q13.13, de novo | Novel | Deleterious/probably damaging | (NM_014191) chr12:52200885(G > A) c.5615G > A/p.R1872Q | Calmodulin-binding motif |
| C0125 | 6 months (F)) | DS | Partial, myoclonic Then tonic | Normal, then spikes,sharp waves and polyspikes (7 months) Slow wave and abnormal background (4 years) | Formation of CSP | OXC, LEV, TPM, then ketogenic diet (slightly-controlled) | (40) 4 y and 2 mo | Moderate | SCN1A 2q24.3, de novo | (Sugawara 2002)3 | Tolerated/probably damaging | (NM_001202435) chr2:166898844(C > T) c.2134C > T/p.R712X | Cytoplasmic domain |
| C0129 | 7 months (M) | DS | Tonic clonic, Febrile convulsions (13 months), tonic, tonic clonic and partial (2y 7months) | Slow-spike-and- wave complexes | Normal | VPA controlled for 1 year, then LEV (controlled, but induced by fever) | (55) 3 y & (52) 5 y | Mild | SCN1A 2q24.3, de novo | Novel | Tolerated/probably damaging | (NM_001202435) chr2:166929907(G > T) c.225G > T/p.E75D | Cytoplasmic domain |
| R1014 | 6 months (M) | DS | Fever-induced tonic or tonic clonic | Normal then spikes, sharp waves and polyspikes (10 months) | Normal | PB, LEV and TPM (slightly-controlled) | (38) 2 y and 6 mo | Moderate | SCN1A 2q24.3, de novo | Novel | Deleterious/probably damaging | (NM_001202435) chr2:166850697(G > A) c.4811G > A/p.W1604X | Ion transport domain |
| C0108 | 3 months (M) | WS | spasms | Hypsarrhythmia | Arachnoid cyst | ACTH,TPM and VPA (refractory seizures) Then TPM, VPA and ketogenic diet (refractory seizures) | (19) 3 y and 10 mo | Severe | STXBP1 9q34.11, de novo | (Allen 2016)4 | Deleterious/probably damaging | (NM_003165) chr9:130438188(C > T) c.1216C > T/p.R406C | Syntaxin-binding protein 1 chain |
| R1007 | 3 months (M) | OS | Spasms | Intermittent burst-suppression during sleep cycle | Ventriculomegaly | VPA and ACTH (refractory seizures) | (36) 1 y | Moderate | STXBP1 9q34.11, de novo | (Allen 2016)4 | Deleterious/probably damaging | (NM_003165) chr9:130438188(C > T) c.1216 C > T/p.R406C | Syntaxin-binding protein 1 chain |
| Likely Pathogenic Variants | |||||||||||||
| C0117 | 7 months (M) | uEEEs | Partial | Slow waves with high amplitude | Ventriculomegaly | VPA, TPM and LEV (refractory seizures) | (44) 1 y and 6 mo | Moderate | SCN1A 2q24.3, NT | Novel | Deleterious/probably damaging | (NM_001202435) chr2:166859090(T > A) c.4176T > A/p.N1392K | Ion transport domain |
| S560 | 1 year (F) | uEEEs | Tonic | Slow-spike-and-wave complexes 100% during NREM sleep cycle | Myelination delay in the cerebral white matter | VPA then LEV and VPA (refractory seizures) | (37) 2 y and 4 mo | Moderate | SCN1A 2q24.3, NT | *** | Deleterious/probably damaging | (NM_001202435) chr2:166900519(G > A) c.1703G > A/p.R568Q | Cytoplasmic domain |
| S569 | 53 days (M) | OS developed to WS | Spasms | Intermittent burst-suppression during sleep cycle | Normal | ACTH and LEV (seizure controlled) then refractory seizures after 4 months. Then LEV and VPA (refractory seizures) SUDEP | (21) 2 y and 6 mo | Severe | ARX Xp21.3, maternal | Novel | Deleterious/probably damaging | (NM_139058) chrX:25022876 (G > C) c.1600G > C/p.A534P | Aristaless domain |
(M) Male; (F) Female; (OS) Ohtarah syndrome; (WS) West syndrome; (DS) Dravet syndrome; (uEEEs) unknown type of early epileptic encephalopathy; (NT) not tested; (SUDEP) sudden unexpected death in epilepsy; (y) year; (mo) month; (ACTH) adrenocorticotropic hormone; (OXC) Oxcarbazepine; (CBZ) Carbamazepine; (LEV) Levetiracetam; (PB) Phenobarbital; (TPM) Topiramate (VPA); Sodium valproate (VPA); (NREM) non-rapid eye movement.
1(Zhao 2014): The variant was reported in variants of CDKL5 and early-onset epileptic encephalopathies or Hanefeld variants of RTT(Rett syndrome); Zhao, Y. et al. Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients. BMC Med. Genet. 25, 15:24 (2014)50.
2(Moulard 2001): The variant was reported in the association between the benign neonatal epilepsy and variants in genes coding for potassium channel subunit KCNQ2; Moulard, B. et al. Ion channel variation causes epilepsies. Brain Res. Brain Res. Rev. 36, 275–284 (2001)51.
3(Sugawara 2002) : The variant was reported in Myoclonic epilepsy of infancy; Sugawara, T. et al. Frequent variants of SCN1A in severe myoclonic epilepsy in infancy. Neurology 58, 1122–1124 (2002)16.
4(Allen 2016): The variant was reported in Unexplained early onset epileptic encephalopathy; Allen, N. M. et al. Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion. Epilepsia 57, e12–7 (2016)31.
***The variant is not reported in HGMD and the ExAC_MAF = 0, but it is reported in dbSNP build 146 rs794727025 dbSNP: rs794727025 Position: chr2:166900519 Band: 2q24.3.
****The variant is not reported in the ExAC, but it is reported in dbSNP build 146 rs118192234 dbSNP: rs118192234 Position: chr20:62044908 Band: 20q13.33.
*****Although parental testing was not available, but since (S559 and C0107) share the same variant (c.1574G > A; p.R525Q) in KCNQ2, since this variant is pathogenic in patient S559, the same variant of patient C0107 was considered pathogenic according to the ACMG Standards and guidelines for the interpretation of sequence variants12.