Table 2

Detailed clinical characterisation of all patients with diagnostic variants in known epilepsy genes

Patient numberSexAge at onset (years)Seizure typeEEGMRIEpilepsy syndromeAED trialsTreatment response (ILAE criteria)16 Family historyGene (transcript) variantsIn silico (CADD, pph2 and SIFT)Allele frequency (gnomAD)Variant classification
12f32Aura with vertigo, dark shadows, sees flashing lights (phosphene), partially followed by impaired consciousness, motionless stare, oral and bilateral hand automatismsIctal: right occipital Interictal: right temporalNormalOLELEV and OXCResistantFather and aunt with seizures DEPDC5
NM_001242896.1:
c.4131delC
p.(Ser1379LeufsTer2)
N/A0P
14f3Focal impaired awareness seizures (motionless stare, feeling of blackening out), BTCSIctal: subclinical occipital (left>right) Interictal: generalisedNormalOLEVPA, PRM, TPM and LEVUndefinedNegative GABRG2
NM_198903.2:
c.1087C>T
p.(Arg363Trp)
33, D, D0LP
24f1Aura with fear, hyperkinetic seizures at night, behavioural arrest, tonic elevation of right leg, BTCS (daily seizures)Ictal: bilateral frontal
Interictal: no changes
NormalFLEPRG, LTG, CBZ and ZNSResistantSister and paternal aunt with focal epilepsy NPRL3
NM_001077350.2:
c.905C>T
p.(Pro302Leu)
33,
D, D
0LP*
25f11Nocturnal hyperkinetic seizures, restlessness, postictal aphasiaIctal: left frontal Interictal: left frontalNormalFLEOXCUndefinedSister with FLE. paternal grandfather and great aunt with epilepsy DEPDC5
NM_001242896.1:
c.381T>A
p.(Tyr127Ter)
35,
N/A
0P
27m19Dystonic posturing of both arms, BTCS, postictal agitation (frequency 5/month)Ictal: right temporal
Interictal: bitemporal
NormalTLELEV, ZNS, CBZ, TPM, GBP and PRGResistantBrother with epilepsy since age of 4 years DEPDC5
NM_001242896.1:
c.4297dupG
p.(Asp1433GlyfsTer26)
N/A0P
32f36Nocturnal seizures with motionless stare, hand automatisms (right), postictal nose wiping (left)Ictal: left temporal
Interictal: left temporal
Left HSTLECBZ, LEV, OXC, PHT, VPA, LTG, GBP and anteromedial TL resectionResistantFather with seizures DEPDC5
NM_001242896.1:
c.1526G>T
p.(Arg509Leu)
16.9,
B, T
0.000004LP*
43m1Behavioural arrest, speech arrest, postictal motor aphasia, rarely BTCSIctal: left temporal
Interictal: left temporal
NormalTLELEV, OXC, LCMResistantNegative DEPDC5
NM_001242896.1:
c.1459C>T
p.(Arg487Ter)
39,
N/A
0P
51m9Epigastric aura, jamais vu, oral automatisms, vocalisation, tonic posturing of both arms (4/month), nocturnal BTCS (1–2/month)Ictal: bilateral
Interictal: bitemporal spikes (left>right)
NormalUFEVPA, LEV and PRGUndefinedMother and maternal uncle with epilepsy DEPDC5
NM_001242896.1:
c.274C>T
p.(Pro92Ser)
29.9,
PD, T
0.000004LP*
56f2Auras with nausea, hypersalivation, vomiting, visual/auditory hallucinations, motionless stare, facial twitching, BTCS (1/year)Ictal: not recorded
Interictal: left frontal
NormalFLETPM, CBZ, LCM, LTG, LEV, VGB and VPAResistantNegative3 Mb microdeletion
Xq21.33-q22.1 (involving PCDH19) chrX:96684649–99663594
N/AN/AP
72f3Focal seizures with visual field restriction, gaze deviation, eyelid twitching, confusion, BTCSIctal: not recorded
Interictal: left frontal
NormalFLELEV, LCM, OXC, FBM and VPAResistantNegative SCN1A
NM_001165963.1:
c.4786C>T;
p.(Arg1596Cys)
35,
D, D
0P
77m9Auras with vertigo, impaired consciousness, motionless stare, BTCSIctal: right temporal
Interictal: bitemporal
NormalTLEVPA, LCM, BRV, ESL, PER, CBZ, PRM, OXC, LTG, anteromedial TL resection (right), DBS implantResistantNegative STX1B
NM_052874.3:
c.537+1G>A
25.8, N/A0LP
81m10Nocturnal seizures with awakening, hypermotor seizures, oral automatisms, bilateral hand automatisms, vocalisation, amnesia, postictal confusion (several seizures per week)Ictal: right hemispheric
Interictal: right frontotemporal spikes
NormalUFECBZ, LEV and TPMResistantNegative380 kb microdeletion
16p13.3
(involving NPRL3) chr16:97 430–4 76 719
N/AN/AP
108m3Head version (changing sides), elevation/extension left arm, flexion of right arm (figure of 4 sign), postictal aphasia, alexia and paresis of right arm, postictal nose wiping, BTCSIctal: not localisable
Interictal: no changes
NormalFLEPHT, LEV, LCM, RUF, ZNS, CBZ, VPA, LTG, PER, VGB, PRM and DBS implantResistantNegative NPRL3
NM_001077350.2:
c.898C>T
p.(Gln300Ter)
39,
N/A
0P
  • Patients with multiple rare variants are highlighted in grey.

  • *GATOR1 complex variant reclassified according to Baldassari et al. 24

  • AED, antiepileptic drug; BRV, Brivaracetam; BTCS, bilateral tonic-clonic seizure; CADD, combined annotation-dependent depletion; CBZ, Carbamazepine; DBS, deep brain stimulation; EEG, electroencephalogram ; ESL, Eslicarbazepine acetate; f, female; FLE, frontal lobe epilepsy; GBP, Gabapentin; gnomAD, Genome Aggregation Database; HS, hippocampal sclerosis; ILAE, International League Against Epilepsy; LCM, Lacosamide; LEV, Levetiracetam; LP, likely pathogenic; LTG, Lamotrigin; m, male; N/A, not applicable; OLE, occipital lobe epilepsy; OXC, Oxcarbazepine; P, pathogenic; PER, Perampanel; PHT, Phenytoin; pph2, PolyPhen-2 (B, benign; D, probably damaging; PD, possibly damaging); PRG, Pregabalin; PRM, Primidone; RUF, Rufinamide; SIFT, sorting intolerant from tolerant (T, tolerated; D, deleterious); TL, temporal lobe; TLE, temporal lobe epilepsy; TPM, Topiramate; UFE, unclassified focal epilepsy; VGB, Vigabatrin; VPA, Valproic acid; VUS, variant of uncertain significance; ZNS, Zonisamide.