Table 2.
SCN2A-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 | |||||
| R19K | N-terminal | Missense | FS+ | Febrile seizures Partial seizure with eye deviation |
(Ito et al., 2004) |
| R36G | N-terminal | Missense | BFIS | Focal seizures Clonic seizures |
(Wolff et al., 2017) |
| I172V | DI (S2) | Missense | FS | Fever-induced seizure susceptibility | (Saitoh et al., 2015a) |
| R188W | DI | Missense | FS+ | Generalized tonic or tonic clonic seizures Partial seizures |
(Ito et al., 2004) |
| A202V | DI | Missense | BFNS | Focal seizures Generalized tonic-clonic seizures |
(Wolff et al., 2017) |
| V208E | DI | Missense | BFIS | NR | (Lemke et al., 2012) |
| R223Q | DI (S4) | Missense | BFNIS | Positive shifts of both activation and inactivation curves | (Berkovic et al., 2004; Scalmani et al., 2006; Zara et al., 2013) |
| D322N | DI (S5-S6) |
Missense | DS | NR | (Shi et al., 2009) |
| F328V | DI (S5-S6) |
Missense |
SMEB |
Status epilepticus Focal seizures Lesions in the right parietal, temporal and occipital lobes (MRI) |
(Shi et al., 2009; Saitoh et al., 2015a) |
| Q383E | DI | Missense | BFNIS | Seizures in early infancy | (Syrbe et al., 2016) |
| E430Q | DI-DII | Missense | BFNIS | Focal spikes and bifrontal slow wave activity (EEG) | (Herlenius et al., 2007) |
| A467T | DI-DII | Missense | GEFS+ | Loss of consciousness Clonic movements of all extremities High body temperature up to 40 ° Celsius |
(Liu et al., 2018) |
| R524Q | DI-DII | Missense | FS | Febrile seizures | (Ito et al., 2004) |
| V892I | DII (S5) | Missense | BFNIS | NR | (Berkovic et al., 2004) |
| N1001K | DII-DIII | Missense | BFIS | Afebrile seizures Tonic body extension Right parietal–occipital sharp waves (EEG) |
(Striano et al., 2006) |
| L1003I | DII-DIII | Missense | BFNIS | Generalized tonic-clonic seizures | (Berkovic et al., 2004) |
| R1319Q | DIII (S4) | Missense |
BFNIS |
Shift steady state activation and inactivation to more positive values | (Berkovic et al., 2004; Scalmani et al., 2006; Misra et al., 2008; Zara et al., 2013) |
| E1321K | DIII | Missense | BFNS | NR | (Grinton et al., 2015) |
| L1330F |
DIII (S4–S5) |
Missense | BFNIS | Shift steady state inactivation to more positive values | (Heron et al., 2002; Scalmani et al., 2006; Misra et al., 2008) |
| L1563V |
DIV |
Missense | BFNIS | Increase in neuronal excitability Accelerated recovery from fast inactivation |
(Heron et al., 2002; Scalmani et al., 2006; Xu et al., 2007; Misra et al., 2008; Berecki et al., 2018) |
| Y1589C | DIV (S2-S3) |
Missense | BFNIS | Increased persistent Na+ current Delayed fast inactivation Acceleration of recovery |
(Lauxmann et al., 2013) |
| I1596S | DIV (S3) | Missense | BFNIS | Central and posterior focal spikes (EEG) | (Herlenius et al., 2007) |
| K1641N | DIV | Missense | BFIS | Focal seizures with secondary generalization | (Zara et al., 2013) |
| De novo mutation | |||||
|
R102X
(Mutation expressed with wild type channel) |
N-terminal | Nonsense | EE | Shift steady state inactivation to more negative values Decrease of available channel |
(Kamiya, 2004; Ogiwara et al., 2009) |
| N132K | DI | Missense | EOEE | Tonic-clonic seizures | (Matalon et al., 2014) |
| M136I | DI | Missense | EIMFS | Focal seizures Spasms |
(Carvill et al., 2013; Howell et al., 2015) |
| E169G | DI (S2) | Missense | EOEE | Multifocal spikes (EEG) Febrile seizure Myoclonic seizure Focal seizure |
(Nakamura et al., 2013) |
| W191C | DI | Missense | EIMFS | Frequent multifocal spikes (EEG) | (Su et al., 2018) |
| F207S | DI | Missense | BNS | Tonic-clonic seizures Clonic seizures |
(Wolff et al., 2017) |
| G211D | DI | Missense | WS | NR | (Kodera et al., 2013) |
| N212D |
DI (S3-S4) |
Missense | OS and WS | Eyelid myoclonic Spasms Hypsarrhythmia |
(Nakamura et al., 2013) |
| R220G | DI | Missense | EE | Generalized tonic-clonic seizures Generalized spike and slow wave (EEG) |
(Mercimek-Mahmutoglu et al., 2015) |
| T227I | DI | Missense | WS | Tonic seizures Apneic seizures Spasms |
(Wolff et al., 2017) |
| T236S | DI (S4-S5) | Missense | OS | Focal seizure | (Nakamura et al., 2013) |
| A240S | DI | Missense | EIMFS | Focal seizures | (Howell et al., 2015) |
| M252V | DI (S5) | Missense | BFNIS | Increased persistent current Accelerated of recovery from fast inactivation Accelerated of recovery from slow inactivation |
(Liao et al., 2010b) |
| V261M | DI (S5) | Missense | BFNIS | Enhanced persistent current Faster recovery from inactivation |
(Liao et al., 2010b) |
| A263T | DI (S5) | Missense | EOEE | Multifocal spikes (EEG) | (Nakamura et al., 2013) |
| V423L |
DI (S6) |
Missense |
OS |
Change in slope of steady-state activation curve Enhanced persistent current |
(Wolff et al., 2017) |
| E430G | DI-DII | Missense | OS | Generalized tonic-clonic seizures | (Matalon et al., 2014) |
| E717G.fs*30 | DI-DII | Splice site | EE Cerebral and cerebellar atrophy |
High amplitude sharp waves (EEG) | (Horvath et al., 2016) |
| G828V | DII | Missense |
BNS |
Focal seizures Clonic seizures Autonomic seizures Tonic-clonic seizures Multifocal spikes (EEG) |
(Wolff et al., 2017) |
| R853Q | DII (S4) | Missense | WS | Reduced transient current amplitude and densityShift steady state inactivation to more negative values Decreased persistent current |
(Samanta and Ramakrishnaiah, 2015; Wolff et al., 2017; Berecki et al., 2018; Mason et al., 2019) |
| R856L | DII | Missense (During embryogenesis) |
EIMFS | Focal seizures | (Howell et al., 2015) |
| R856Q | DII | Missense | OS | Tonic seizures | (Wolff et al., 2017) |
| S863F | DII | Missense | BNS and Focal epilepsy | Generalized tonic-clonic seizures | (Wolff et al., 2017) |
| I873M | DII | Missense | EIEE | Abnormal electroretinogram | (Trump et al., 2016) |
| N876T | DII (S4-S5) |
Missense | OS and WS | Spasms Focal seizure |
(Nakamura et al., 2013) |
|
L881P |
DII | Missense | WS and LGS | Tonic seizures Tonic-clonic seizures Atypical absences |
(Wolff et al., 2017) |
| G882R | DII | Missense | EIMFS | Unilateral tonic-clonic | (Wolff et al., 2017) |
|
G882E |
DII | Missense | EIMFS | Focal seizures Autonomic seizures Hemiclonic seizures Myoclonic seizures Clonic seizures |
(Wolff et al., 2017) |
| V887A | DII | Missense | OS | Spasms | (Wolff et al., 2017) |
| G899S |
DII (S5) |
Missense | Intractable infantile Childhood epilepsy |
Tonic-clonic seizures and absences Shift steady-state activation to more positive values Increased slop factor |
(Wolff et al., 2017) |
| K905N | DII | Missense | EIMFS | Focal seizures | (Carvill et al., 2013; Howell et al., 2015) |
| F928C | DII | Missense | EIMFS | Focal seizures | (Carvill et al., 2013; Howell et al., 2015) |
| H930Q | DII | Missense |
MAE |
Tonic-clonic seizures Atonic seizures Myoclonic-atonic seizures Tonic seizures Atypical absences |
(Wolff et al., 2017) |
| N976K | DII | Missense | EE | Focal seizures | (Howell et al., 2015) |
| S987I | DII | Missense | EIEE | Focal and tonic seizures | (Trump et al., 2016) |
| G999L | DII-DIII | Missense | Infantile epilepsy | Diffuse slowing with high-amplitude bursts of activity (EEG) Generalized seizures with burst suppression |
(Foster et al., 2017) |
| E999K | DII-DIII | Missense | EIEE | NR | (Trump et al., 2016) |
| E999V | DII-DIII | Missense | EIEE OS |
NR | (Allen et al., 2016; Trump et al., 2016) |
| I1021Y.fs*16 | DII-DIII | Frameshift | LGS | NR | (Carvill et al., 2013) |
| E1211K |
DIII (S1) |
Missense | WS | Shift steady-state activation and inactivation to more negative values Slower recovery from inactivation |
(Ogiwara et al., 2009; Wong et al., 2015) |
| K1260E and K1260Q (Mosaic) | DIII | Missense | EIEE | NR | (Trump et al., 2016) |
| R1312T |
DIII (S4) |
Missense | DS | Reduced current density Shift steady-state activation and inactivation to more negative values Enhanced closed-state inactivation Slowed recovery from inactivation |
(Shi et al., 2009; Lossin et al., 2012) |
| M1323V |
DIII (S4-S5) |
Missense | OS and WS | Multifocal spikes (EEG) | (Nakamura et al., 2013) |
| V1326D | DIII | Missense | EIMFS | Focal seizures | (Dhamija et al., 2013) |
| S1336Y | DIII (S4-S5) |
Missense | OS and WS | Modified hypsarrhythmia | (Nakamura et al., 2013) |
| M1338T | DIII (S4-S5) |
Missense | OS | Spasms Focal seizure Multifocal spikes (EEG) |
(Nakamura et al., 2013) |
| L1342P | DIII | Missense | IOEE | Progressive brain atrophy Short tonic seizures Multifocal sharp wave activity (EEG) |
(Hackenberg et al., 2014) |
| I1473M | DIII (S6) | Missense | SNEE | Shift steady-state inactivation to more negative values | (Ogiwara et al., 2009) |
| Q1479P | DIII | Missense | EIEE | NR | (Trump et al., 2016) |
| V1528Cfs*7 | DIII-DIV | Frameshift | LGS | Tonic-clonic seizures Tonic seizures Status epilepticus |
(Wolff et al., 2017) |
| Q1531K | DIII-DIV | Missense | BNS | Clonic seizures Generalized tonic-clonic seizures |
(Wolff et al., 2017) |
| I1537S and M1538I | DIV | Missense | OS and WS | Clonic seizures Frequent seizure activity (EEG) |
(Foster et al., 2017) |
| M1548V | DIV | Missense |
OS and WS |
Generalized tonic-clonic seizures | (Wolff et al., 2017) |
| G1593R | DIV | Missense | EIMFS | Focal seizures | (Howell et al., 2015) |
| F1597L |
DIV (S3) |
Missense | EIMFS | Shift steady-state activation to more negative values accelerated recovery from fast inactivation |
(Wolff et al., 2017) |
| D1598G | DIV (S3) | Missense |
SME |
Severe intellectual disability Developmental delay Seizures/ infantile spasms |
(Need et al., 2012) |
| P1622S | DIV (S3-S4) |
Missense |
MAE |
Shift steady-state inactivation to more negative values | (Wolff et al., 2017) |
| T1623N | DIV (S3-S4) |
Missense | OS and WS | Multifocal spikes (EEG) Spasms Hypsarrhythmia |
(Nakamura et al., 2013) |
| V1627M | DIV | Missense | EIMFS | Focal seizures Apnoeic seizures |
(Wolff et al., 2017) |
| G1634V | DIV | Missense | OS | Focal seizures Spasms |
(Howell et al., 2015) |
| I1640S | DIV | Missense | EE | Tonic seizures Focal seizues |
(Wolff et al., 2017) |
| L1650P | DIV | Missense | EIEE | NR | (Trump et al., 2016) |
|
A1652P |
DIV | Missense |
WS |
Spasms | (Wolff et al., 2017) |
| S1656F | DIV | Missense | LGS | Generalized tonic-clonic seizures | (Wolff et al., 2017) |
| L1660T | DIV (S4-S5) |
Missense | EE | Generalized tonic-clonic seizures | (Fukasawa et al., 2015) |
| L1660W | DIV | Missense | Acute encephalopathy | Tonic-clonic convulsions Frequent spikes and sharp waves in the right fronto-temporal regions (EEG) Cerebellar atrophy (MRI) |
(Fukasawa et al., 2015) |
| Q1811E | C-terminal | Missense |
OS |
Generalized tonic-clonic seizures Focal seizures |
(Wolff et al., 2017) |
| L1829F | C-terminal | Missense | EIEE | NR | (Trump et al., 2016) |
| H1853R | C-terminal | Missense | OS | Generalized tonic-clonic seizures Absence seizures |
(Martin et al., 2014) |
| R1882L | C-terminal | Missense | Epilepsy | Generalized and irregular spike wave and polyspike wave activity (EEG) Focal and generalized tonic–clonic seizures with opisthotonus, bradycardia, and cyanosis |
(Baasch et al., 2014) |
| R1882G | C-terminal | Missense | BIS | Shift steady-state inactivation to more positive values Increase current density and protein production |
(Carvill et al., 2013; Schwarz et al., 2016; Wolff et al., 2017) |
| R1882Q | C-terminal | Missense | EIEE | Increased current density Enhanced persistent current |
(Trump et al., 2016; Berecki et al., 2018; Mason et al., 2019) |
|
D25Nβ1
β1 subunit mutation* |
β subunit | Substitution * human embryonic kidney 293 (HEK) cells co-expressing human Nav1.2 sodium channels and D25Nβ1 |
GEFS+ | Inhibits the increment of functional expression of NaCh currents Abolishes the shift of the voltage dependence of activation and inactivation |
(Baroni et al., 2018) |
|
Chromosome 2q24.3
Portions of the SCN2A and SCN3A genes |
Chromosome | Deletion (112-kb) |
Mental retardation Infantile seizures |
Anxiety disorders ‘shiver-like’ episodes |
(Bartnik et al., 2011) |
|
Chromosome q24.3q31.1
58 known genes including SCN2A, SCN1A, SCN3A, SCN9A and SCN7A |
Chromosome | Deletion (10.29 - 10.58 Mb) |
Severe epilepsy | Focal and generalized seizures Stereotypic and repetitive hand movements Slow background with high amplitude delta waves mixed with spikes and sharp waves on the temporo-occipital areas (EEG) |
(Pescucci et al., 2007) |
| Non genetic origin mutations reported* | |||||
| V213D | DI (S4) | Missense | EOEE | Focal seizure Focal spikes (EEG) |
(Nakamura et al., 2013) |
| T218K | DI | Missense | EIMFS | Focal seizures Spasms |
(Howell et al., 2015) |
| D649N | DI-DII | Missense | DS | NR | (Wang et al., 2012) |
| V752F | DI-DII | Missense | Absence epilepsy | Increased current density Shift steady-state activation and inactivation to more negative values |
(Oliva et al., 2014) |
| M1128T | DII-DIII | Missense | AERRPS | Generalized convulsive seizure Slow background activity and rare multifocal spikes over the right temporal and bilateral frontopolar regions (EEG) Brain edema (Cranial computed tomography) |
(Kobayashi et al., 2012) |
| G1522A | DIII-DIV | Missense | EE | Absence seizures Generalized spike and waves (EEG) |
(Mercimek-Mahmutoglu et al., 2015) |
| R1629L | DIV (S4) | Missense | EOEE | Focal seizure Burst of spikes (EEG) |
(Nakamura et al., 2013) |
| R1918H | C-terminus | Missense | GEFS+ | Generalized tonic-clonic seizures | (Haug et al., 2001) |
| GAL879-881QQQ | DII (S4-S5) (rat brain) | Mutated channel in transgenic mice | Epilepsy | Delayed fast inactivation Increased persistent current when expressed in Xenopus oocytes |
(Kearney et al., 2001) |
| R85Cβ1 | Extracellular immunoglobulin-like domain (β1 subunit) |
Substitution *Human embryonic kidney (HEK)-293T cells co-expressing human brain NaV1.2 alpha subunit and R85Cβ1 |
GEFS+ | Fail to modulate fast inactivation kinetics Fail to modulated steady-state inactivation |
(Xu et al., 2007) |
| R85Hβ1 | Extracellular immunoglobulin-like domain (β1 subunit) |
Substitution *Human embryonic kidney (HEK)-293T cells co-expressing human brain NaV1.2 alpha subunit and R85Hβ1 |
GEFS+ | Fail to modulated fast inactivation kinetics | (Xu et al., 2007) |
|
C121Wβ1
β1 subunit mutation* |
Ig-like domain (β1 subunit) |
Substitution * Chinese hamster ovary (CHO) cells co-expressing human Nav1.2 sodium channels and C121Wβ1 |
GEFS+ | Destabilization of steady-state inactivation potentials Disrupts the thermoprotective role of the β1 subunit on channel availability |
(Egri et al., 2012; Abdelsayed and Sokolov, 2013) |
|
Chromosome 2q24.3
Involves the SCN2A and SCN3A genes |
Chromosome | Duplication (1.77 Mb) |
EOEE | Multifocal spikes (EEG) Epileptic spasms |
(Baumer et al., 2015) |
|
Chromosome 2q24.3- q31.1
47 genes involved including SCN1A, SCN2A, SCN3A, SCN7A and SCN9A |
Chromosome | Deletion (10.4-Mb) |
Severe epilepsy | Epileptic seizure with pale, atonic periods followed by a spasm-like out-throwing of both arms Predominantly right-sided epileptiform activity (EEG) |
(Davidsson et al., 2008) |
*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+); Benign familial neonatal-infantile seizures (BFNIS); Benign familial neonatal seizures (BFNS); Benign Familial Infantile Seizures (BFIS); Benign neonatal/infantile seizures (BNIS); Benign neonatal seizures (BNS); Benign infantile seizures (BIS); Febrile seizures (FS); Febrile seizures plus (FS+); Epilepsy of infancy with migrating focal seizures (EIMFS); Ohtahara syndrome (OS); West syndrome (WS); Lennox-Gastaut syndrome (LGS); Dravet syndrome (DS); Borderline severe myoclonic epilepsy (SMEB); Severe myoclonic epilepsy (SME); Early-onset epileptic encephalopathies (EOEE); Acute encephalitis with refractory, repetitive partial seizures (AERRPS); Early infantile epileptic encephalopathy (EIEE); myoclonic-atonic epilepsy; Infantile onset epileptic encephalopathy (IOEE); Sporadic neonatal epileptic encephalopathy (SNEE); Epileptic encephalopathy (EE); Not Reported (NR); Domain (D); Segment (S); Electroencephalography (EEG); Magnetic resonance imaging (MRI).