SCN2A. This is the Epilepsiome page for SCN2A, one of the most common genetic causes for neurodevelopmental disorders, including epileptic encephalopathies. The phenotypic spectrum ranges from BFNIS, to autism/intellectual disability/schizophrenia, infantile spasms and severe early-onset epileptic encephalopathies.
Here are the most recent blog posts that mention SCN2A
- SCN2A – This is what you need to know in 2015
- Story of a genetic shape-shifter: SCN2A in benign seizures, autism and epileptic encephalopathy
- From zero to one hundred in the genetics of Febrile Seizures
- SCN2A takes center stage again as an autism gene
In a nutshell. SCN2A is one of the most common causes of neurodevelopmental disease. Phenotypes include BFNIS, autism/intellectual disability/schizophrenia, infantile spasms progressing to epileptic encephalopathy and severe early-onset epileptic encephalopathy. Movement disorders seem to be common in patients with epileptic encephalopathy. SCN2A encodes an alpha subunit in a voltage-gated sodium channel and is pivotal for neuronal signaling. However, functional aspects remain to be elucidated and there is currently no good mouse model available. Some recurrent variants exist within the encephalopathy spectrum and seem to display a kind of genotype-phenotype correlation but further studies are needed to show if these correlations will prove true over time.
|Phenotypes||Genetics||Mechanism & Function|
|The Clinical Perspective||Community||Resources & References|
General overview. There is no comprehensive overview of SCN2A phenotypes available to date, and the full spectrum of neurodevelopmental disorders due to variants in this gene is not fully understood. Based on current understanding of the literature, we can breakdown the SCN2A phenotypes into four different groups including (1) benign neonatal or infantile epilepsies, (2) neurodevelopmental/neuropsychiatric disorders, including schizophrenia, autism and intellectual disability, (3) Infantile Spasms, and (4) early onset epileptic encephalopathies, including Ohtahara syndrome, Dravet syndrome, West syndrome and severe neonatal epilepsies. All phenotypes within the SCN2A spectrum can be conceptualized along three dimensions including (a) cognitive outcome, (b) seizures, and (c) movement disorders. Here are the main phenotypes of this spectrum, given in historical order.
Benign familial neonatal/infantile seizures (BFNIS). The familial syndrome of benign familial neonatal/infantile seizures was the first SCN2A phenotype to be described, and it is probably the least common presentation of an SCN2A mutation. Mutations were identified in large families where affected individuals had neonatal and/or infantile seizures and a normal neurodevelopmental outcome. This familial form of SCN2A has been reported in independent studies after the initial discovery, but it became obvious quickly that this familial syndrome is much less common than familial neonatal seizures due to mutation in KCNQ2 or infantile seizures due to PRRT2. Also, this phenotype can be seen in families with SCN8A mutations.
Autism, intellectual disability, schizophrenia. After the initial discovery of SCN2A as a gene associated with BFNIS, it became silent around SCN2A. Interestingly, this gene re-emerged as one of the most obvious candidate genes in many neurodevelopmental disorders in large exome studies. Several studies found de novo variants in SCN2A in patients with neurodevelopmental/neuropsychiatric phenotypes including intellectual disability, autism, and schizophrenia. SCN2A variants associated with these conditions are usually truncating, suggesting that haploinsufficiency plays a major role.
Infantile Spasms. We have broken down the epileptic encephalopathy phenotypes caused by variants in SCN2A in two broad categories – epileptic encephalopathies presenting with Infantile Spasms (usually at the age of 3-6 months) or severe epilepsies starting earlier. Even though there is probably a gradient between both phenotypes, we felt that breaking down the SCN2A epileptic encephalopathies into two major categories may make sense from a clinical perspective, as we usually think about different causes for seizures in children presenting with epilepsy as neonates compared to the epilepsy in children developing Infantile Spasms after an initial normal development. With regard to Infantile Spasms, it is interesting to note that the patients in the Epi4K publication (Infantile Spasms) had the identical p.R853Q variant, suggesting the existence of some genotype/phenotype correlation. Some patients with SCN2A-related Infantile Spasms are also reported to have movement disorders, including late onset episodic ataxia and myoclonus.
Severe early-onset epileptic encephalopathies. There is an entire spectrum of severe epilepsies due to pathogenic variants in SCN2A that start neonatally or within the first two months of life. For some epilepsies, it is possible to classify them into known epilepsy syndromes, such as West syndrome, Ohtahara syndrome or Dravet syndrome. For other epilepsies, a classification is more difficult, and these conditions are referred to as unclassified epileptic encephalopathies. Again, movement disorders seem to be common in this group of severe epilepsies. As of 2015, there is no established genotype/phenotype correlation, complicating the interpretation of genetic findings in this group of epilepsies.
Other phenotypes. SCN2A variants have also been reported in a small number of patients with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), but the pathogenicity of at least one of these variants has been questioned. At least one of these reported patients had a unaffected parent who had the same variant, making it unclear whether or not the SCN2A variant was truly disease-causing. In addition, SCN2A variants have been reported in at least 4 individuals with neonatal onset (1st week to month of life) of focal or generalized seizures with onset of episodic ataxia in early childhood. Recurrent seizures resolved in all patients by around 1 year of age.
Mutational spectrum. Over 90 different potential disease-causing variants have been reported in SCN2A. The vast majority of these variants are heterozygous missense variants, most of which are associated with an epilepsy phenotype, and have only been reported in a single patient or family. Nonsense variants have also been reported in patients with epilepsy, intellectual disability, and/or autism. A smaller number of splice site and frameshift variants, as well as large exonic or whole gene deletions and duplications, have also been identified in patients with various SCN2A-associated phenotypes. Variants have been reported throughout the SCN2A gene. Table 1 lists some of the disease-causing variants reported in SCN2A. This list is only a small representation of the variants found in this gene. There is currently no publicly available SCN2A-related gene database that includes all published variants. Organizing this data in a phenotype-specific way is part of our Epilepsiome project. Some of the information about de novo variants was taken from the most recent download of the NPdenovo database (see attached table). All annotations were re-annotated with wANNOVAR and SCN2A:NM_001040143 was used as a reference. This list of variants is incomplete and will be expanded in the future to provide you with a better idea about the spectrum of SCN2A-related disorders.
Table 1. Variants in SCN2A and their associated phenotypes (NM_021007.2).
Genotype-Phenotype Correlation. No definite genotype-phenotype correlation has been identified for SCN2A variants to date, and many variants have only been identified in a single patient or family. However, a small number of recurrent variants have been identified in multiple patients with the same phenotype, suggesting that a genotype-phenotype correlation may exist. De novo missense and truncating variants are usually associated with a more severe phenotype, while inherited missense variants are usually associated with milder phenotypes, such as BFNIS. For neurodevelopmental disorders other than epilepsy, variants seem to be protein-disrupting. Truncating variants are generally not observed in patients with epilepsy phenotypes. Some of the variants seen in epileptic encephalopathies are recurrent, suggesting that other mechanisms such as dominant-negative or activating mechanisms are involved.
General Considerations for Variant interpretation. When reviewing a genetic variant to determine its significance for a given patient, it is important to weigh multiple pieces of evidence:
Considerations for gene level interpretation. First, it is important to establish the strength of the evidence showing that the gene is associated with epilepsy. Some genes may only have one variant reported in a single individual with epilepsy, while other genes may have multiple variants reported in many large families with an autosomal dominant pattern of epilepsy. For SCN2A, there is very strong evidence for its role in human epilepsy.
Considerations for variant level interpretation. When reviewing the significance of a variant, it is important to consider the impact on the gene and the presence of the variant in previously described patient and control populations. Many clinical genetic testing laboratories classify genetic variants into different categories, ranging from benign to pathogenic. Variants that are common in control populations and would not be predicted to have a major impact on the gene/protein are generally classified as benign. Variants are more likely to be classified as pathogenic if the variants are rare or not present in the control population, reported in multiple individuals or families with disease, and likely to have a higher impact on the gene/protein based on the type of mutation or functional studies. Variants with uncertain or limited available evidence may be classified as variants of uncertain significance (VUS), indicating that further information is required in order for the variant to be further defined. In some cases, testing additional family members can be helpful, as it allows the lab to determine whether or not the variant was inherited (versus de novo) and how the variant segregates with disease in the family. Sometimes further classification of a VUS requires waiting for the identification of additional patients or families with similar or nearby variants. The considerations for SCN2A variant interpretation are complex given the heterogeneity of phenotypes.
Inheritance, Penetrance & Prevalence. SCN2A variants can be de novo or inherited. With the exception of the BFNIS-associated alterations which are inherited in an autosomal dominant pattern, most SCN2A variants appear to be sporadic and de novo. The penetrance of SCN2A-associated phenotypes appears to be high. Considerable variable expressivity, particularly in seizure type and severity, can occur. SCN2A variants and their associated phenotypes are rare, but the exact prevalence is unknown.
Haploinsuffiency or dominant negative. SCN2A codes for the voltage-gated sodium channel, neuronal type II, alpha subunit. The SCN2A protein is located at the axon initial segment, the key structure in neurons where the decision is made whether the addition of all excitatory and inhibitory inputs will result in the firing of an action potential. Therefore, the function of SCN2A is pivotal to neurons. While the loss of function obviously results in haploinsufficiency for SCN2A as seen in some patients with autism and intellectual disability, the functional impact of other variants is less clear. There is some suggestion that the missense variants seen in patients with epileptic encephalopathies are activating whereas some of the BFNIS mutations have reduced cell surface expression, resulting in a net loss of SCN2A function. Systematic data on a battery of SCN2A variants implicated in human epilepsy is currently not readily available, leaving some of the functional aspects difficult to address.
Mice. The SCN2A mouse model (Q54) presents with seizures and episodic behavioral arrest with stereotypical behaviors, such as tail wagging, head bobbing and chewing. Mice eventually developed frequent spontaneous generalized tonic-clonic seizures that resulted in premature death (Kearney et al, 2001).
Recurrence Risk & Testing of Family Members. SCN2A variants can be de novo or inherited in an autosomal dominant pattern. If a variant in SCN2A is detected in an unaffected parent, this variant is inherited and may be an innocent bystander, meaning the patient may have a different disease-causing variant in another gene. Some SCN2A variants are recurrent and may therefore be considered pathogenic without parental confirmation. Each child of an individual with a disease-causing variant has a 50% (1 in 2) of inheriting the disease-causing variant and an equal chance of inheriting the functional (wild-type) copy of the gene. Germline mosaicism of an SCN2A variant has been reported, making the recurrence risk for families with a child with a de novo variant with an SCN2A variant higher than the general population risk.
Therapy. There is no gene- or mutation-specific therapy recommended for treatment of SCN2A-associated phenotypes at this point in time. A study by Nakamura and collaborators suggested that lamotrigine may be beneficial in patients with transmembrane variants, but additional studies are needed to confirm this observation. Given the vast genetic and phenotypic heterogeneity of SCN2A phenotypes and the variability of seizure phenotypes even in patients with identical variants, a variety of AED effects have been reported that may not be necessarily related to the underlying disease-causing variant. However, given the expanding number of patients with identified SCN2A variants, identifying gene- or variant-specific drug responses is an active field of research in the epilepsy genetics community.
Research studies. The scientific community is currently actively studying SCN2A and its role in human disease. The SCN2A Epilepsiome team is happy to facilitate if you have questions or a specific interest in this gene.
Patient registry. The FamiliesSCN2A Foundation has partnered with Simons VIP Connect on their registry. Learn more at http://www.scn2a.org/ or https://simonsvipconnect.org/.
SCN2A Genetics Home Reference https://ghr.nlm.nih.gov/gene/SCN2A
Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscular hypotonia, and brain abnormalities.
Baasch AL, Hüning I, Gilissen C, Klepper J, Veltman JA, Gillessen-Kaesbach G, Hoischen A, Lohmann K.
Epilepsia. 2014 Apr;55(4):e25-9.
Benign familial neonatal-infantile seizures: characterization of a new sodium channelopathy.
Berkovic SF, Heron SE, Giordano L, Marini C, Guerrini R, Kaplan RE, Gambardella A, Steinlein OK, Grinton BE, Dean JT, Bordo L, Hodgson BL, Yamamoto T, Mulley JC, Zara F, Scheffer IE.
Ann Neurol. 2004 Apr;55(4):550-7.
Mutation screening of SCN2A in schizophrenia and identification of a novel loss-of-function mutation.
Carroll LS, Woolf R, Ibrahim Y, Williams HJ, Dwyer S, Walters J, Kirov G, O’Donovan MC, Owen MJ.
Psychiatr Genet. 2016 Apr;26(2):60-5.
Novel de novo SCN2A mutation in a child with migrating focal seizures of infancy.
Dhamija R, Wirrell E, Falcao G, Kirmani S, Wong-Kisiel LC.
Pediatr Neurol. 2013 Dec;49(6):486-8.
Autism in several members of a family with generalized epilepsy with febrile seizures plus.
Dixon-Salazar TJ, Keeler LC, Trauner DA, Gleeson JG.
J Child Neurol. 2004 Aug;19(8):597-603.
De novo nonsense mutations in the sodium channel gene, SCN2A, in sporadic intractable epilepsy.
Clin Genet. 2010 Jun;77(6):538-40.
A case of recurrent encephalopathy with SCN2A missense mutation.
Fukasawa T, Kubota T, Negoro T, Saitoh M, Mizuguchi M, Ihara Y, Ishii A, Hirose S.
Brain Dev. 2015 Jun;37(6):631-4.
Infantile epileptic encephalopathy, transient choreoathetotic movements, and hypersomnia due to a De Novo missense mutation in the SCN2A gene.
Hackenberg A, Baumer A, Sticht H, Schmitt B, Kroell-Seger J, Wille D, Joset P, Papuc S, Rauch A, Plecko B.
Neuropediatrics. 2014 Aug;45(4):261-4.
The voltage-gated sodium channel gene SCN2A and idiopathic generalized epilepsy.
Haug K, Hallmann K, Rebstock J, Dullinger J, Muth S, Haverkamp F, Pfeiffer H, Rau B, Elger CE, Propping P, Heils A.
Epilepsy Res. 2001 Dec;47(3):243-6.
Hlf is a genetic modifier of epilepsy caused by voltage-gated sodium channel mutations.
Hawkins NA, Kearney JA.
Epilepsy Res. 2016 Jan;119:20-3.
SCN2A mutations and benign familial neonatal-infantile seizures: the phenotypic spectrum.
Herlenius E, Heron SE, Grinton BE, Keay D, Scheffer IE, Mulley JC, Berkovic SF.
Epilepsia. 2007 Jun;48(6):1138-42.
Sodium-channel defects in benign familial neonatal-infantile seizures.
Heron SE, Crossland KM, Andermann E, Phillips HA, Hall AJ, Bleasel A, Shevell M, Mercho S, Seni MH, Guiot MC, Mulley JC, Berkovic SF, Scheffer IE.
Lancet. 2002 Sep 14;360(9336):851-2. Erratum in: Lancet 2002 Nov 9;360(9344):1520.
SCN2A encephalopathy: A major cause of epilepsy of infancy with migrating focal seizures.
Howell KB, McMahon JM, Carvill GL, Tambunan D, Mackay MT, Rodriguez-Casero V, Webster R, Clark D, Freeman JL, Calvert S, Olson HE, Mandelstam S, Poduri A, Mefford HC, Harvey AS, Scheffer IE.
Neurology. 2015 Sep 15;85(11):958-66.
Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.
Jiang YH, Yuen RK, Jin X, Wang M, Chen N, Wu X, Ju J, Mei J, Shi Y, He M, Wang G, Liang J, Wang Z, Cao D, Carter MT, Chrysler C, Drmic IE, Howe JL, Lau L, Marshall CR, Merico D, Nalpathamkalam T, Thiruvahindrapuram B, Thompson A, Uddin M, Walker S, Luo J, Anagnostou E, Zwaigenbaum L, Ring RH, Wang J, Lajonchere C, Wang J, Shih A, Szatmari P, Yang H, Dawson G, Li Y, Scherer SW.
Am J Hum Genet. 2013 Aug 8;93(2):249-63.
A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline.Kamiya K, Kaneda M, Sugawara T, Mazaki E, Okamura N, Montal M, Makita N, Tanaka M, Fukushima K, Fujiwara T, Inoue Y, Yamakawa K.
J Neurosci. 2004 Mar 17;24(11):2690-8.
A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities. Kearney JA, Plummer NW, Smith MR, Kapur J, Cummins TR, Waxman SG, Goldin AL, Meisler MH.
Scn2a sodium channel mutation results in hyperexcitability in the hippocampus in vitro.
Kile KB, Tian N, Durand DM.
Epilepsia. 2008 Mar;49(3):488-99.
Acute encephalopathy with a novel point mutation in the SCN2A gene.
Kobayashi K, Ohzono H, Shinohara M, Saitoh M, Ohmori I, Ohtsuka Y, Mizuguchi M.
Epilepsy Res. 2012 Nov;102(1-2):109-12.
SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain.
Liao Y, Anttonen AK, Liukkonen E, Gaily E, Maljevic S, Schubert S, Bellan-Koch A, Petrou S, Ahonen VE, Lerche H, Lehesjoki AE.
Neurology. 2010 Oct 19;75(16):1454-8.
Molecular correlates of age-dependent seizures in an inherited neonatal-infantile epilepsy.Liao Y, Deprez L, Maljevic S, Pitsch J, Claes L, Hristova D, Jordanova A, Ala-Mello S, Bellan-Koch A, Blazevic D, Schubert S, Thomas EA, Petrou S, Becker AJ, De Jonghe P, Lerche H.
Brain. 2010 May;133(Pt 5):1403-14.
Confirming an expanded spectrum of SCN2A mutations: a case series.
Matalon D, Goldberg E, Medne L, Marsh ED.
Epileptic Disord. 2014 Mar;16(1):13-8.
Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome.
Nakamura K, Kato M, Osaka H, Yamashita S, Nakagawa E, Haginoya K, Tohyama J, Okuda M, Wada T, Shimakawa S, Imai K, Takeshita S, Ishiwata H, Lev D, Lerman-Sagie T, Cervantes-Barragán DE, Villarroel CE, Ohfu M, Writzl K, Gnidovec Strazisar B, Hirabayashi S, Chitayat D, Myles Reid D, Nishiyama K, Kodera H, Nakashima M, Tsurusaki Y, Miyake N, Hayasaka K, Matsumoto N, Saitsu H.
Neurology. 2013 Sep 10;81(11):992-8.
De novo mutations of voltage-gated sodium channel alphaII gene SCN2A in intractable epilepsies.
Ogiwara I, Ito K, Sawaishi Y, Osaka H, Mazaki E, Inoue I, Montal M, Hashikawa T, Shike T, Fujiwara T, Inoue Y, Kaneda M, Yamakawa K.
Neurology. 2009 Sep 29;73(13):1046-53.
Missense mutations in sodium channel SCN1A and SCN2A predispose children to encephalopathy with severe febrile seizures.
Saitoh M, Ishii A, Ihara Y, Hoshino A, Terashima H, Kubota M, Kikuchi K, Yamanaka G, Amemiya K, Hirose S, Mizuguchi M.
Epilepsy Res. 2015 Nov;117:1-6.
Severe epilepsy, retardation, and dysmorphic features with a 2q deletion including SCN1A and SCN2A.
Pereira S, Vieira JP, Barroca F, Roll P, Carvalhas R, Cau P, Sequeira S, Genton P, Szepetowski P.
Neurology. 2004 Jul 13;63(1):191-2.
Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia.
Schwarz N, Hahn A, Bast T, Müller S, Löffler H, Maljevic S, Gaily E, Prehl I, Biskup S, Joensuu T, Lehesjoki AE, Neubauer BA, Lerche H, Hedrich UB.
J Neurol. 2016 Feb;263(2):334-43.
Clinical spectrum of SCN2A mutations.
Shi X, Yasumoto S, Kurahashi H, Nakagawa E, Fukasawa T, Uchiya S, Hirose S.
Brain Dev. 2012 Aug;34(7):541-5.
Missense mutation of the sodium channel gene SCN2A causes Dravet syndrome.Shi X, Yasumoto S, Nakagawa E, Fukasawa T, Uchiya S, Hirose S.
Brain Dev. 2009 Nov;31(10):758-62..
A novel SCN2A mutation in family with benign familial infantile seizures.
Striano P, Bordo L, Lispi ML, Specchio N, Minetti C, Vigevano F, Zara F.
Epilepsia. 2006 Jan;47(1):218-20.
A missense mutation of the Na+ channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction.
Sugawara T, Tsurubuchi Y, Agarwala KL, Ito M, Fukuma G, Mazaki-Miyazaki E, Nagafuji H, Noda M, Imoto K, Wada K, Mitsudome A, Kaneko S, Montal M, Nagata K, Hirose S, Yamakawa K.
Proc Natl Acad Sci U S A. 2001 May 22;98(11):6384-9. Erratum in: Proc Natl Acad Sci U S A 2001 Aug 28;98(18):10515.
Whole genome sequencing identifies SCN2A mutation in monozygotic twins with Ohtahara syndrome and unique neuropathologic findings.
Touma M, Joshi M, Connolly MC, Grant PE, Hansen AR, Khwaja O, Berry GT, Kinney HC, Poduri A, Agrawal PB.
Epilepsia. 2013 May;54(5):e81-5.
Sodium channels SCN1A, SCN2A and SCN3A in familial autism.
Weiss LA, Escayg A, Kearney JA, Trudeau M, MacDonald BT, Mori M, Reichert J, Buxbaum JD, Meisler MH.
Mol Psychiatry. 2003 Feb;8(2):186-94.
Paternal germline mosaicism of a SCN2A mutation results in Ohtahara syndrome in half siblings.
Zerem A, Lev D, Blumkin L, Goldberg-Stern H, Michaeli-Yossef Y, Halevy A, Kivity S, Nakamura K, Matsumoto N, Leshinsky-Silver E, Saitsu H, Lerman-Sagie T.
Eur J Paediatr Neurol. 2014 Sep;18(5):567-71.
The SCN2A Epilepsiome Team