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SCN2A-Related Disorders SCN2A Explained The Genetics of SCNA2 SCN2A Spectrum of Autism and Epilepsy SCN2A Comorbidities Clinical Information Key Publications Glossary

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SCN2A has been called a “genetic shape shifter”. The SCN2A gene is located on the long (q) arm of chromosome 2 at position 24.3. The SCN2A gene encodes (contains instructions for) the NaV1.2 sodium channel which plays a key role in both action potential propagation (signaling) in neurons and synaptic plasticity (learning). Pathogenic variants (mutations that affect SCN2A gene expression) impact the flow of sodium ions across the surfaces of neurons. Some pathogenic variants reduce the number of NaV1.2 channels present on the neuron cell surface, leading to an autism phenotype +/- epilepsy. Other variants cause abnormal or increased flow of sodium ions across channels, leading to epilepsy. Gene location - long (q) arm of chromosome 2 at position 24.3 Patterns of inheritance - autosomal dominant; frequently de novo Prevalence: Over 1,000 cases of SCN2A-related disorders have been identified to date, with an estimated prevalence of ~8 in 100,000 Presentation Gain of Function (GoF): these pathogenic SCN2A variants often cause changes in the NaV1.2 channels, such that sodium ion flow is increased or unregulated and are associated with severe, early-onset (<3 months of life) epilepsy Loss of Function (LoF): these pathogenic SCN2A variants often cause a decrease in the number of NaV1.2 channels on the neuron cell surface, affecting neuron signaling and plasticity, and are associated with an ASD phenotype, with or without epilepsy Mixed Function: these pathogenic variants have a wider range of effects on the NaV1.2 protein and are associated with a range of phenotypes, both epilepsy and ASD Genotype / phenotype is well established Learn more: FamilieSCN2A: The Genetics of SCN2A Video: The genetics and physiology of SCN2A in autism and early-onset seizures

Diagnostic Testing Genetic testing is essential in diagnosis of SCN2A-related disorders (SRDs) and is also critical for determining the SCN2A clinical phenotype and guiding effective treatment. Not all SCN2A variants are pathogenic, and consultation with a genetic counselor or geneticist can be helpful in determining whether a genetic change is causing an individual’s clinical symptoms. Once a genetic diagnosis of an SCN2A-related disorder is made, an individual may be referred to a specialist depending on their clinical presentation. Diagnostic Guidelines Cambridge Elements: SCN2A-Related Disorders Children’s Hospital of Philadelphia - SCN2A Diagnosis and Testing Testing References National Library of Medicine Genetic Testing Registry - SCN2A ClinVar Rare Epilepsies Network (REN) and Orphan Drug Center Single Gene Tests and Panels Invitae Beyond the Seizure Program Invitae - SCN2A Invitae Epilepsy Panel Invitae Cerebral Palsy Spectrum Disorders Panel Invitae Rett and Angelman Syndromes and Related Disorders Panel Invitae Neurodevelopmental Disorders (NDD) Panel Genetic sequencing GeneDx - Exome Sequencing Rare Genomes Project - Whole Genome Sequencing SPARK - Simons Powering Autism Research Probably Genetic - Whole Exome Sequencing for rare diseases Variant mapping SCN2A Variant Viz from UCSF Psychiatry Bioinformatics Core Other genetic testing resources Little Zebra Fund

Clinical Information

Comprehensive resources to help clinicians and other professionals working with people with SRDs.

d o n a t e

SCN2A Resources for Clinicians

SCN2A encodes a voltage-gated sodium channel (designated NaV1.2) vital for generating neuronal action potentials. Pathogenic SCN2A variants are associated with a diverse array of neurodevelopmental disorders featuring neonatal or infantile onset epilepsy, developmental delay, autism, intellectual disability and movement disorders. SCN2A is a high confidence risk gene for autism spectrum disorder and a commonly discovered cause of neonatal onset epilepsy. This remarkable clinical heterogeneity is mirrored by extensive allelic heterogeneity and complex genotype-phenotype relationships partially explained by divergent functional consequences of pathogenic variants. Emerging therapeutic strategies targeted to specific patterns of NaV1.2 dysfunction offer hope to improve the lives of individuals affected by SCN2A-related disorders.”

2024 Cambridge Elements - Genetics in Epilepsy - SCN2A-Related Disorders

Key Considerations

Presentation

Genetics

Seizures

Treat aggressively to achieve seizure freedom
Monitor closely for drug efficacy and toxicity
Seizure control may be related to prognosis
Efficacy of medications may vary by phenotype (presentation)
USE CAUTION when treating patients with Loss of Function variants, as sodium channel blockers may be contraindicated

Multidisciplinary care is needed to provide optimal support

Presentation & Comorbidities

2024 Cambridge Elements - Genetics in Epilepsy - SCN2A-Related Disorders. Figure 4 Clinical spectrum of SCN2A-related disorders. "Black-shaded boxes indicate phenotypes associated with normal development. Unshaded boxes indicate phenotypes associated with mild or moderate to severe or profound ID. Arrows indicate predominant associated functional effects of SCN2A variants in each condition. Typical age of onset is given in months (m) and generally refers to the onset of seizures.”

Three major phenotypes:

Self-limited familial neonatal-infantile epilepsy (SeLFNIE)
Developmental and Epileptic Encephalopathy (DEE)
Autism Spectrum Disorder / Intellectual Disability (ASD/ID)

Emerging phenotypes

Schizophrenia

Note: Not all people with SRDs present with seizures; seizures may develop later in life or not at all

Comorbidities

Autism Spectrum Disorder
Autonomic Dysfunction
Cerebral Palsy (spasticity, hypotonia)
Cortical Vision Impairment
Epilepsy
- - Benign Familial Infantile Seizures
  - Early Infantile Epileptic Encephalopathy (e.g. Ohtahara & West Syndrome)
  - Later onset epilepsy with ASD
  - Lennox-Gastaut Syndrome
  - Migrating Partial Epilepsy of Infancy
GI Dysfunction (Reflux & constipation)
Intellectual Disability
Movement Disorders (chorea, ataxia, dystonia)
Neuropathic Pain
Sleep Disorders
Speech and Language Deficit
Urology problems (infections & urinary retention)

For comprehensive clinical care guidelines, please visit 2024 Cambridge Elements - Genetics in Epilepsy - SCN2A-Related Disorders

Learn More

ICD-10 Code: QA0.0101 (effective Oct 1, 2025)

ICD-10 Codes

EFFECTIVE October 1, 2025: New ICD-10 code for SCN2A Neurodevelopmental Disorders is QA0.0101

Using the correct ICD codes helps with insurance payments, research efforts, surveillance, epidemiology, health system utilization measurements, and clinical trial enrollment.

SCN2A-specific code

2025 - new code (QA0.010 goes into effect on October 1, 2025)

2023 - ICD-10 Coordination and Maintenance Committee Meeting to consider SCN2A-specific code

CDC - Full meeting agenda (SCN2A on pages 113 - 116); CDC - Meeting Exerpt - SCN2A agenda

2021 - FamilieSCN2A Foundation applied for new SCN2A-specific code

Coding best practices:

QA0.0101 is not meant to replace other condition codes; rather, it is used in addition to other codes for related disorders such as epilepsy and autism spectrum disorder.
List codes for associated medical conditions and/or intellectual disabilities.
Condition and symptom codes are still needed for proper insurance reimbursement of rehabilitation and other services (i.e. hypotonia code for PT).
For consistency among providers, please document new codes in patient’s electronic health record.
Encourage families to share new codes with all providers, including urgent / emergency care providers. FamilieSCN2A Foundation will take the lead in providing education and promotion materials.

Genetics

SCN2A has been called a “genetic shape shifter”.

The SCN2A gene is located on the long (q) arm of chromosome 2 at position 24.3. The SCN2A gene encodes (contains instructions for) the NaV1.2 sodium channel which plays a key role in both action potential propagation (signaling) in neurons and synaptic plasticity (learning). Pathogenic variants (mutations that affect SCN2A gene expression) impact the flow of sodium ions across the surfaces of neurons. Some pathogenic variants reduce the number of NaV1.2 channels present on the neuron cell surface, leading to an autism phenotype +/- epilepsy. Other variants cause abnormal or increased flow of sodium ions across channels, leading to epilepsy.

Gene location - long (q) arm of chromosome 2 at position 24.3
Patterns of inheritance - autosomal dominant; frequently de novo
Prevalence: Over 1,000 cases of SCN2A-related disorders have been identified to date, with an estimated prevalence of ~8 in 100,000
Presentation
- Gain of Function (GoF): these pathogenic SCN2A variants often cause changes in the NaV1.2 channels, such that sodium ion flow is increased or unregulated and are associated with severe, early-onset (<3 months of life) epilepsy
- Loss of Function (LoF): these pathogenic SCN2A variants often cause a decrease in the number of NaV1.2 channels on the neuron cell surface, affecting neuron signaling and plasticity, and are associated with an ASD phenotype, with or without epilepsy
- Mixed Function: these pathogenic variants have a wider range of effects on the NaV1.2 protein and are associated with a range of phenotypes, both epilepsy and ASD
Genotype / phenotype is well established

Learn more:

FamilieSCN2A: The Genetics of SCN2A

Video: The genetics and physiology of SCN2A in autism and early-onset seizures

Diagnostic Testing

Diagnostic Testing

Genetic testing is essential in diagnosis of SCN2A-related disorders (SRDs) and is also critical for determining the SCN2A clinical phenotype and guiding effective treatment. Not all SCN2A variants are pathogenic, and consultation with a genetic counselor or geneticist can be helpful in determining whether a genetic change is causing an individual’s clinical symptoms. Once a genetic diagnosis of an SCN2A-related disorder is made, an individual may be referred to a specialist depending on their clinical presentation.

Diagnostic Guidelines

Cambridge Elements: SCN2A-Related Disorders
Children’s Hospital of Philadelphia - SCN2A Diagnosis and Testing

Testing References

Single Gene Tests and Panels

Genetic sequencing

GeneDx - Exome Sequencing
Rare Genomes Project - Whole Genome Sequencing
SPARK - Simons Powering Autism Research
Probably Genetic - Whole Exome Sequencing for rare diseases

Variant mapping

SCN2A Variant Viz from UCSF Psychiatry Bioinformatics Core

Other genetic testing resources

Little Zebra Fund

Clinical Care & Specialists

Given the complexity of SCN2A-related disorders, clinical care teams are often multi-disciplinary, emphasizing the importance of coordinated efforts to optimize care and minimize clinical risks. SCN2A Multidisciplinary Care Centers are clinical care settings where the clinicians have expertise in treating SCN2A-related disorders. MDCs are also places where individuals with SRDs can participate in research studies and found out about new therapies.

SCN2A Multidisciplinary Care Centers

Epilepsy Specialty Care Centers with experience treating children with SCN2A related epilepsy

Telehealth Precision Genetic Counseling for Epilepsy and Neurodevelopmental Disorders

University of Texas Health Science Center at Houston

International Clinicians

(Shared by partner organizations; not vetted by The FamilieSCN2A Foundation)

Europe

Common Specialists Seen by Individuals with SCN2A-Related Disorders

Many individuals with SCN2A-related disorders are seen by the following specialty fields:

Neurology
Genetics
Developmental Pediatrics
Psychiatry / Psychology / Neuropsychology
Speech, Occupational, Physical, and Vision Therapy
Behavioral Therapy

Some individuals with SCN2A-related disorders are seen by additional specialists beyond the above list, depending on their comorbidities.

Specialists include:

Endocrinology
Gastroenterology
Immunology
Ophthalmology
Orthopedics
Pulmonology
Urology

Medically complex care:

Individuals with epilepsy/DEE may be followed by a Complex Care Team and/or Case Management. Consultation with child life specialists and palliative care teams may be indicated to enhance quality of life.

Treatments and Therapies

Treatments / Therapies

For individuals with SCN2A-related disorders who experience seizures/epilepsy, the following principles generally apply in choice of antiepileptic drugs (AEDs). However, there is much complexity in the treatment of SCN2A-related epilepsy, so a pediatric neurologist with SCN2A experience or an SCN2A Multidisciplinary Care Center should be consulted whenever possible.

Gain of Function Phenotype (typically very early epilepsy onset, <3 months of life, severe epilepsy): Ideally AED regimen will include sodium channel-blocking medications, such as phenytoin, lacosamide, oxcarbazepine, carbamazepine, lamotrigine, and zonisamide.
Loss of Function Phenotype (typically later-onset, >3 months of life, epilepsy): Generally avoid sodium channel-blocking medications and choose alternative AEDs
Mixed Phenotype: Consult a pediatric neurologist or Multidisciplinary Care Center with expertise in SCN2A, as these clinical phenotypes are more varied in response to AEDs

For comprehensive clinical care guidelines, please visit 2024 Cambridge Elements - Genetics in Epilepsy - SCN2A-Related Disorders

Learn More:

Epilepsy Foundation - Summary of Anti-seizure Medications

Clinical Trials & Experimental Treatments

Opportunities to participate in research, including access to experimental treatments.

Clinical trial opportunities

FamilieSCN2A website:

ClinicalTrials.gov:

Limited opportunities for select patients working with clinician researchers

Individualized ASO treatment

n-lorem

Mutation
c.2558 G>A; p.Arg853Gln
c.5645 G>A; p.Arg1882Gln
ASO Strategy
Allele-selective
ASO Treatment Therapy

From n-Lorem: We have a therapy available for a nano-rare patient with a mutation in the SCN2A gene that has the potential to help other patients with a mutation in this gene. If you are a patient or patient family or a physician of a potential patient, please email us at info@nlorem.org for more information on this program.

Drug repurposing

EveryCure

Clinicians using off-label drugs to treat people with SCN2A-related disorders are encouraged to share ideas with EveryCure.

Learn More:

Emerging Disease-Modifying Therapies sections of 2024 Cambridge Elements - Genetics in Epilepsy - SCN2A-Related Disorders

Medical & Emergency Protocols

Action plans and products to prevent and respond to emergencies.

Protocol Repositories

Condition-specific Protocols

Epilepsy

Autism