Five Variants in SCN8A Associated with Neurodevelopmental Disorders and Epileptic Encephalopathy

The SCN8A gene is well-established as being associated with a broad range of neurodevelopmental disorders (NDDs), including epilepsy, autism spectrum disorder (ASD), and developmental delays. Variants in SCN8A are linked to diverse clinical phenotypes, ranging from severe epileptic encephalopathy to milder developmental and intellectual disabilities. This week's #FiveVariantsFriday features SCN8A variants identified in patients with complex phenotypes that are notably absent from ClinVar as of October 18, 2024.

Although SCN8A is a well-recognized gene with known links to neurodevelopmental disorders, many key variants have not yet been added to ClinVar. This highlights the importance of using multiple resources, including  Adenine AI , in addition to ClinVar, for gathering and interpreting genetic evidence. Tools like  Adenine AI  bring together evidence from diverse sources, providing a more comprehensive picture. In this article, we explore five SCN8A variants absent from ClinVar, a common scenario across many genes, which underscores the need for a multi-database approach to ensure more accurate and thorough variant classification.

1. Ataxia and Diplopia Linked to SCN8A

• PMID: 37440794
• Mutation: SCN8A:c.2540G>A (p.Arg847Gln)
• Case: A 10-year-old girl with episodes of transient ataxia, diplopia, and dysmetria during febrile illnesses but no seizures. This case introduces a unique SCN8A-related phenotype where symptoms mimic ataxia without the typical seizure manifestations.

2. Novel SCN8A Variant in Pediatric Epilepsy

• PMID: 37498161
• Mutation: SCN8A:c.4499C>T (p.Pro1500Leu)
• Case: An 8-year-old boy with epilepsy, intellectual disability, and autism spectrum disorder. This variant, while found in a healthy mother and classified as uncertain, highlights the need for further exploration into the genotype-phenotype correlation of SCN8A mutations.

3. Multiple SCN8A Variants in Chinese Patients

• PMID: 28923014
• Mutations:
  • SCN8A:c.694T>C (p.Ser232Pro)
  • SCN8A:c.2549G>A (p.Arg850Glu)
  • SCN8A:c.5614C>T (p.Arg1872Trp)
  • SCN8A:c.423G>A (p.Gly1475Arg)
  • SCN8A:c.5630A>G (p.Asn1877Ser)
  • SCN8A:c.4793T>C (p.Val1598Ala)
• Case: In this study, six de novo SCN8A mutations were identified in patients with diverse epilepsy presentations, broadening the phenotypic spectrum of SCN8A-related disorders, which includes cases of benign infantile seizures and severe encephalopathy. Two variants are although present in ClinVar and pointing to the right article, other variants are absent.

4. Severe Bone Loss in SCN8A-Related Epileptic Encephalopathy

• PMID: 28676440
• Mutation: SCN8A:c.1078_1079delTTinsGC (p.Phe360Ala)
• Case: A 6-year-old girl presented with epileptic encephalopathy alongside juvenile osteoporosis and multiple fractures, pointing to broader systemic impacts of SCN8A mutations. This study sheds light on skeletal fragility as a rare comorbidity.

5. Neurotransmitters and SCN8A-Related Channelopathies

• PMID: 29184379
• Mutations:
  • SCN8A:c.5615G>A (p.Arg1872Gln)

• Case: A patient with de novo mutations in SCN8A were studied for neurotransmitter abnormalities. The patient showed decreased levels of key neurotransmitters like homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA). 

These cases exemplify the phenotypic diversity associated with SCN8A variants. The use of Adenine AI was crucial in streamlining the collection of genetic evidence, allowing for a comprehensive understanding of these mutations and their clinical implications. For more detailed insights, explore our full article.

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