Table 1.
SCN1A-related epilepsies identified in clinical patients through WES and/or NGS.
| Variant | Location | Mutation | Disease | Alteration on biophysical properties or/and Clinical report | Reference |
|---|---|---|---|---|---|
| Inherited mutation | |||||
| A27T | N-terminal | Missense | GEFS+SMEB | Diffuse spikes, prevailing in posterior regions (EEG) | (Nicita et al., 2010) |
| L61P | N-terminal | Missense | DS | Febrile seizures | (Halvorsen et al., 2016) |
| F63L | N-terminal | Missense | DS | Severe developmental delay Spike and Waves in right fronto-temporal region with spreading (EEG) |
(Nicita et al., 2010) |
| F90S | N-terminal | Missense | DS | Multifocal spikes, frontal-dominant spike-waves complex (EEG) | (Sun et al., 2008; Wang et al., 2012; Xu et al., 2014; Butler et al., 2017b) |
| S103G | N-terminal | Missense | SME DS |
Ataxia Rare-spike wave complex (EEG) |
(Fujiwara, 2003; Ebrahimi et al., 2010; Tonekaboni et al., 2013) |
| S106F | N-terminal | Missense | Focal epilepsy | Right temporal parietal occipital slow-wave and generalized spike-wave complex (EEG) | (Barba et al., 2014) |
| M145T | DI (S1) | Missense | Unidentified epilepsy | Decrease current density Shift steady-state inactivation to more positive values |
(Mantegazza et al., 2005; Colosimo et al., 2007) |
| L193F | DI (S3) | Missense | GEFS+ | Generalized tonic–clonic seizures | (Cui et al., 2011) |
| V244L | DI (S4-S5) | Missense | DS | Myoclonic seizures Generalized spikes or spike-and-wave complexes in the interictal (EEG) |
(Morimoto et al., 2006) |
| R377Q | DI (S5-S6) | Missense | GEFS+ | Generalized tonic-clonic seizures | (Zucca et al., 2008; Xu et al., 2015; Cetica et al., 2017; Lindy et al., 2018) |
| F412I | DI (S6) | Missense | SMEB GEFS+ |
Febrile seizure | (Ebrahimi et al., 2010; Tonekaboni et al., 2013) |
| K488EfsX6 | DI-DII | FrameShift | DS | NR | (Yang et al., 2017) |
| R542Q | DI-DII | Missense | GEFS+ SME |
NR | (Escayg et al., 2001; Weiss et al., 2003; Combi et al., 2009; Orrico et al., 2009; Wang et al., 2012; Lee et al., 2014; Lal et al., 2016) |
| R618C | DI-DII | Missense | PEFS+ | Generalized tonic-clonic seizures Multifocal epilepsy and bilateral bursts of 3-4 Hz spike and wave (EEG) |
(Brunklaus et al., 2015) |
| Y790C | DII (S1-S2) | Missense | GEFS+ | Decreased current density Decreased of cell surface expression |
(Annesi et al., 2003; Orrico et al., 2009; Bechi et al., 2015; Bennett et al., 2017) |
| R859H | DII (S4) | Missense | GEFS+ | Shift steady state activation and inactivation to more negative values Enhanced Persistent current |
(Volkers et al., 2011; Myers et al., 2017a; Lindy et al., 2018) |
| S1084C | DII-DIII | Missense | Juvenile myoclonic epilepsy DS |
Paroxysmal generalised polyspike-and- wave complexes with myoclonic seizures (EEG) | (Jingami et al., 2014) |
| T1174S | DII-DIII | Missense | FHM FS |
Shift steady state activation to more positive values Deceleration of recovery from fast inactivation Increase of persistent current |
(Escayg et al., 2001; Gargus and Tournay, 2007; Yordanova et al., 2011; Rilstone et al., 2012; Cestèle et al., 2013; Lal et al., 2016) |
| V1353L | DIII (S5) | Missense | PEFS+ GEFS+ |
Non-functional channel | (Wallace et al., 2001; Lossin et al., 2003; Bennett et al., 2017) |
| A1429S | DIII (S5-S6) |
Missense | Autossomal dominant nocturnal frontal lobe epilepsy | No definitive epileptic spikes (EEG) | (Sone et al., 2012) |
| R1596H | DIV (S2-S3) |
Missense | GEFS+ | Generalized spike-wave complexes (EEG) Normal imaging (MRI) |
(Hoffman-Zacharska et al., 2015) |
| I1656M | DIV (S4) | Missense | GEFS+ | Shift steady state activation to more positive values | (Lossin et al., 2003) |
| G1674S | DIV (S5) | Missense | FS+ | Febrile seizure Hemiconvulsion |
(Saitoh et al., 2015a) |
| De novo mutation | |||||
| Q3X | N-terminal | Nonsense | DS | Generalized tonic clonic seizures | (Claes et al., 2003; Lim et al., 2011) |
| G58X | N-terminal | Nonsense | DS Focal Epilepsy |
Autistic characteristics; Hyperactivity Periventricular nodular heterotopia (MRI) |
(Barba et al., 2014) |
| Y65X | N-terminal | Nonsense | DS | Generalized tonic-clonic seizures | (Zucca et al., 2008) |
| E75D | N-terminal | Missense | DS | Slow-spike-wave complexes (EEG) | (Arafat et al., 2017) |
| L80_D81del | N-terminal | Inframe deletion | DS | Pharmacoresistant | (Usluer et al., 2016) |
| D81N | N-terminal | Missense | DS | Severe Motor and mental delay Multi-focal spike-waves (EEG) |
(Usluer et al., 2016) |
| I91T | N-terminal | Missense | DS | Frontal-dominant spike-waves complex (EEG) | (Sun et al., 2008; Xu et al., 2014) |
| G96EfsX24 | N-terminal | FrameShift | NR | Genetic generalized epilepsy with intellectual disability | (Fry et al., 2016) |
| R101Q | N-terminal | Missense | DS SMEB GEFS+ PEFS+ |
Psychomotor retardation | (Fukuma et al., 2004; Harkin et al., 2007; Marini et al., 2007; Depienne et al., 2008; Sun et al., 2010; Zuberi et al., 2011; Wang et al., 2012; Tonekaboni et al., 2013; Lee et al., 2014; Djémié et al., 2016) |
| A104V | N-terminal | Missense | DS | Epileptic discharges, slow spike and weave; sharp wave, sharp and slow wave complex (EEG) | (Kwong et al., 2012; Myers et al., 2017a) |
| R118S | N-terminal | Missense | DS | Generalized tonic-clonic seizures Severe mental retardation |
(Zucca et al., 2008) |
| F144YfsX5 | DI (S1) | Frameshift | SME DS |
Moderate psychomotor retardation | (Fukuma et al., 2004; Zuberi et al., 2011; Wang et al., 2012; Villeneuve et al., 2014) |
| M145DfsX4 | DI (S1) | Frameshift | PEFS+ | Generalized tonic-clonic seizures without any provoked factors | (Yu et al., 2010) |
| G177E | DI (S2-S3) | Missense | SME DS |
Non-functional channel | (Nabbout et al., 2003; Ohmori et al., 2006; Usluer et al., 2016) |
| L180X | DI (S2-S3) | Nonsense | DS | Focal spike wave (EEG) | (Liu et al., 2018) |
| W190X | DI (S3) | Nonsense | DS | Febrile, partial, generalized tonic-clonic and myo-clonic seizures Severe intellectual disability |
(Marini et al., 2007; Kwong et al., 2012) |
| S213W | DI (S3-S4) | Missense | Epilepsy | Febrile and afebrile seizures Developmental delay |
(Butler et al., 2017a) |
| R219SfsX57 | DI (S4) | FrameShift | DS | Generalized tonic-clonic seizures | (Claes et al., 2001) |
| R222X | DI (S4) | Nonsense | DS SMEB |
No measurable current | (Claes et al., 2001; Nabbout et al., 2003; Fukuma et al., 2004; Harkin et al., 2007; Depienne et al., 2008; Orrico et al., 2009; Zuberi et al., 2011; Wang et al., 2012; Xu et al., 2014; Esterhuizen et al., 2018) |
| I227S | DI (S4) | Missense | SME SMEB |
Epileptiform discharges on both sides and spikes/polyspikes during photic stimulation (EEG) Low current density (no detectable) |
(Nabbout et al., 2003; Ohmori et al., 2006; Depienne et al., 2008; Mak et al., 2011; Wang et al., 2012; Lindy et al., 2018) |
| A239V | DI (S4-S5) | Missense | SME DS |
Focal right fronto-temporal spikes with spreading (EEG) Severe developmental delay |
(Iannetti et al., 2009; Nicita et al., 2010; Xu et al., 2014) |
| W280R | DI (S5-S6) | Missense | DS | Febrile seizures Status epilepticus Myoclonic Multifocal discharges (EEG) |
(Nabbout et al., 2003; Wang et al., 2012; Liu et al., 2018) |
| P281L | DI (S5-S6) | Missense | DS | Moderate mental retardation | (Depienne et al., 2008; Gokben et al., 2017; Lindy et al., 2018) |
| E311X | DI (S5-S6) | Nonsense | DS | Haploinsufficiency | (Orrico et al., 2009) |
| G329A | DI (S5-S6) | Missense | GEFS+ | Generalized tonic–clonic seizures | (Myers et al., 2017a) |
| G343E | DI (S5-S6) | Missense | SMEB SME DS |
Spike-wave complex, Multifocal spikes (EEG) |
(Fujiwara, 2003; Depienne et al., 2008; Zuberi et al., 2011) |
| D366E | DI (S5-S6) | Missense | DS | Generalized tonic-clonic seizures | (Zucca et al., 2008) |
| W384R | DI (S5-S6) | Missense | DS SMEB SME |
Generalized tonic-clonic seizures Partial seizures |
(Zuberi et al., 2011; Wang et al., 2012; Verbeek et al., 2013) |
| T391P | DI (S5-S6) | Missense | DS | Generalized tonic-conic seizures Partial Seizures |
(Reyes et al., 2011) |
| R393H | DI (S5-S6) | Missense | DS SMEB |
Generalized tonic-clonic seizures Myoclonus, Febrile seizures Developmental delay |
(Claes et al., 2003; Marini et al., 2007; Sun et al., 2010; Zuberi et al., 2011; Lemke et al., 2012; Rilstone et al., 2012; Wang et al., 2012; Xu et al., 2014; Djémié et al., 2016; Haginoya et al., 2018) |
| V422L | DI (S6) | Missense | EE | Psychomotor developmental delay Theta activities with right predominance (EEG) |
(Ohashi et al., 2014) |
| Y426N | DI-DII | Missense | DS | Decreased current density shift stead-state inactivation to more negative values Delayed recovery from inactivation |
(Nabbout et al., 2003; Ohmori et al., 2006; Allen et al., 2016) |
| L433fsX16 | DI-DII | FrameShift | Myoclonic astatic epilepsy | Generalized tonic-clonic seizures | (Ebach et al., 2005) |
| E435X | DI-DII | Nonsense | DS | Myoclonic seizures Atypical absence |
(Fukuma et al., 2004; Wang et al., 2012) |
| Q554H | DI-DII | Missense | DS | Generalized tonic-clonic seizure Atonic and myoclonic seizures |
(Skjei et al., 2015) |
| S662X | DI-DII | Nonsense | PEFS+ | Generalized tonic-clonic seizures | (Yu et al., 2010) |
| W738X | DI-DII | Nonsense | SME | Febrile seizures Generalized tonic-clonic Severe intellectual disability |
(Kwong et al., 2012; Xu et al., 2014) |
| T808S | DII (S2) | Missense | ICEGTC | Rare sharp waves in left temporal (EEG) Increase current density Delay recovery from inactivation |
(Fujiwara, 2003; Rhodes et al., 2005) |
| S843X | DII (S3) | Nonsense | DS | Focal spike activity (EEG) |
(Buoni et al., 2006) |
| R862G | DII (S4) | Missense | MMPSI | Multifocal epilepsy Hemiclonic Cardiac arrest Severe intellectual disability |
(Carranza Rojo et al., 2011; Barba et al., 2014) |
| T932X | DII (S5-S6) | Nonsense | SME DS |
Generalized tonic-clonic seizures Severe mental retardation |
(Claes et al., 2003; Dhamija et al., 2014) |
| M934I | DII (S5-S6) | Missense | DS | Moderate psychomotor retardation | (Fukuma et al., 2004; Depienne et al., 2008; Wang et al., 2012) |
| H939Q | DII (S5-S6) | Missense | DS | Status epilepticus Generalized tonic-clonic seizures Complex partial seizures No measurable current |
(Claes et al., 2003; Ohmori et al., 2006) |
| R946C | DII (S5-S6) | Missense | SME DS SMEB |
Non- functional Channel | (Fukuma et al., 2004; Volkers et al., 2011; Zuberi et al., 2011; Wang et al., 2012; Lee et al., 2014; Xu et al., 2014; Lindy et al., 2018) |
| R946S | DII (S5-S6) | Missense | Severe idiopathic generalized epilepsy of infancy | Short generalized tonic-clonic seizures at night Seizure onset left temporo-parietal (EEG) Seizure onset left frontal Seizure onset right frontocentral, |
(Ebach et al., 2005; Tiefes et al., 2019) |
| R946H | DII (S5-S6) | Missense | PEFS+ SMEB DS |
Non-functional Channel | (Fukuma et al., 2004; Harkin et al., 2007; Depienne et al., 2008; Liao et al., 2010a; Verbeek et al., 2011; Volkers et al., 2011; Zuberi et al., 2011; Wang et al., 2012; Verbeek et al., 2013) |
| C959R | DII (S5-S6) | Missense | DS | Post trauma epilepsy Lateralized tonic-clonic seizures Severe mental retardation Non-functional Channel |
(Claes et al., 2003; Ohmori et al., 2006) |
| V971L | DII (S6) | Missense | DS | Generalized and unilateral tonic-clonic seizures Myoclonic seizures Apneic spells |
(Poryo et al., 2017) |
| V982L | DII (S6) | Missense | SMEB | Focal epilepsy | (Singh et al., 2009; Saitoh et al., 2012; Saitoh et al., 2015a; Saitoh et al., 2015b) |
| V983A | DII (S6) | Missense | ICEGTC | Multifocal spikes, high voltage slow-waves (EEG) Reduced current density Shift steady-state inactivation to more positive values Accelerated recovery from inactivation |
(Fujiwara, 2003; Rhodes et al., 2005) |
| V983AfsX2 | DII (S6) | FrameShift | DS | Enlarged extracerebral gap (MRI) | (Wang et al., 2017b) |
| L986F | DII (S6) | Missense | DS | Generalized tonic-clonic seizures Non-functional channel |
(Claes et al., 2001; Lossin et al., 2003) |
| L991VfsX2 | DII (S6) | FrameShift | DS | Febrile, partial, generalized tonic-clonic, myo-clonic seizures Moderate intellectual disability. |
(Kwong et al., 2012) |
| N1011I | DII-DIII | Missense | ICEGTC | Rare sharp waves in lateral-temporal (EEG) Reduced current density Shift steady state inactivation to more negative values |
(Fujiwara, 2003; Rhodes et al., 2005) |
| D1046MfsX9 | DII-DIII | FrameShift | DS | Diffuse cerebral edema (Computed tomography) | (Myers et al., 2017b) |
| S1100KfsX8 | DII-DIII | FrameShift | DS | Generalized clonic seizures Severe mental retardation |
(Claes et al., 2001) |
| S1104X | DII-DIII | Missense | DS | Febrile seizures | (Depienne et al., 2008; Hernández Chávez et al., 2014) |
| E1153X | DII-DIII | Nonsense | DS | Focal epilepsy with frontal-lateral activity (EEG) | (Hernández Chávez et al., 2014) |
| E1176NfsX32 | DII-DIII | FrameShift | DS | Severe intellectual disability Intractable seizures despite multiple anti-epileptic drugs |
(Willemsen et al., 2012) |
| R1213X | DII-DIII | Nonsense | SME DS LGS |
Rare spikes, multifocal spikes and spike-wave complex (EEG) Severe mental delay |
(Fujiwara, 2003; Depienne et al., 2008; Zuberi et al., 2011; Wang et al., 2012; Allen et al., 2013; Xu et al., 2014; Lindy et al., 2018) |
| L1230P | DIII (S1) | Missense | DS | Focal spike-wave complex (EEG) Febrile seizures Myoclonic seizures |
(Liu et al., 2018) |
| F1263L | DIII (S2) | Missense | SMEB | Rare spike-wave complex and poly spike-waves complex (EEG) | (Fujiwara, 2003) |
| R1636Q | DIV (S4) | Missense | DS LGS |
Epileptic encephalopathy Myoclonic seizures |
(Harkin et al., 2007; Butler et al., 2017b) |
| V1637E | DIV (S4) | Missense | DS | Episodes of status epilepticus triggered by fever |
(Nishri et al., 2010; Zuberi et al., 2011) |
| F1671fsX8 | DIV (S4-S5) |
FrameShift | DS | Generalized tonic-clonic seizures Severe mental retardation |
(Claes et al., 2001; Sugawara et al., 2002; Depienne et al., 2008; Riva et al., 2009) |
| A1685D | DIV (S5) | Missense | DS | Spike-wave complex (EEG) Non-functional channel |
(Fujiwara, 2003) (Sugiura et al., 2012) |
| Y1694C | DIV (S5) | Missense | DS | Myoclonic seizures Atypical absence Severe psychomotor retardation |
(Fukuma et al., 2004; Wang et al., 2012; Cetica et al., 2017) |
| L1717P | DIV (S5-S6) |
Missense | SME | Generalized tonic clonic seizure | (Verbeek et al., 2013) |
| T1722A | DIV (S5-S6) |
Missense | DS | Myoclonic, hemiclonic, focal seizures | (Wu et al., 2015) |
| C1741S | DIV (S5-S6) |
Missense | TLE-MTS | Febrile status epilepticus | (Tiefes et al., 2019) |
| G1754R | DIV (S5-S6) |
Missense | DS | Focal seizures Hemiconvulsions |
(Petrelli et al., 2012) |
| S1768R | DIV (S6) | Missense | DS | Absences and tonic-clonic seizures | (Willemsen et al., 2012) |
| E1881X | C-terminal | Nonsense | DS SMEB |
Febrile and generalized seizures | (Villeneuve et al., 2014) |
| Non genetic origin mutations reported* | |||||
| G177DfsX4 | DI (S2-S3) | FrameShift | DS | Generalized tonic-clonic seizures | (Fujiwara, 2003) |
| V207G | DI (S3) | Missense | EE | Early-onset multifocal seizures | (Daoud et al., 2016) |
| D249E | DI (S4-S5) | Missense | DS | Generalized tonic seizures Absences; Mental retardation |
(Le Gal et al., 2014) |
| N275K | DI (S5) | Missense | PEFS+ | Hippocampal volume loss (MRI) | (Kim et al., 2014) |
| T363R | DI (S5-S6) | Missense | DS | Generalized tonic-clonic seizures | (Zuberi et al., 2011; Le Gal et al., 2014) |
| N416I | DI (S6) | Missense | DS | Focal spike-wave (EEG) | (Zhou et al., 2018) |
| S1631C | DIV (S3-S4) |
Missense | DS | Multifocal spikes (EEG) | (Haginoya et al., 2018) |
*Non genetic origin mutations reported: Mutations described through clinical diagnosis, but the mutation type (Mendelian or de novo) were not reported, mainly due to the lack of parents to perform genotyping and difficulty in contacting the family. Generalized epilepsy with febrile seizures plus (GEFS+); Febrile seizures (FS); Febrile seizures plus (FS+); Lennox-Gastaut syndrome (LGS); Dravet syndrome (DS); Borderline severe myoclonic epilepsy (SMEB); Severe myoclonic epilepsy (SME); Familial hemiplegic migraine (FHM); Partial epilepsy with antecedent FS (PEFS+); Intractable childhood epilepsy with generalized tonic–clonic seizures (ICEGTC); Intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC); Epileptic encephalopathy (EE); Malignant migrating partial seizures of infancy (MMPSI); Temporal lobe epilepsy (TLE); Mesial temporal sclerosis (MTS); Not Reported (NR); Domain (D); Segment (S); Electroencephalography (EEG); Magnetic resonance imaging (MRI).