SCN1B – Developmental and Epileptic Encephalopathy

SCN1B encodes the β1 subunit of voltage-gated sodium channels, modulating neuronal excitability. Biallelic pathogenic variants in SCN1B are linked to early-onset developmental and epileptic encephalopathy (Developmental and Epileptic Encephalopathy). This autosomal recessive disorder presents in infancy with myoclonic and generalized tonic-clonic seizures, status epilepticus, and subsequent global developmental impairment.

Autosomal recessive inheritance is supported by compound heterozygous and homozygous SCN1B variants in affected individuals. Three probands from two families (index case with p.Arg85Cys/c.3G>C and two siblings homozygous for c.265C>T (p.Arg89Cys)) demonstrate concordant phenotypes ([PMID:36291443]; [PMID:31465153]). Segregation analysis identified two additional affected siblings with homozygosity for c.265C>T (p.Arg89Cys) in one pedigree, confirming recessive transmission.

Variant spectrum in SCN1B-related encephalopathy predominantly comprises missense changes within the extracellular immunoglobulin domain leading to loss of function. A representative variant, c.265C>T (p.Arg89Cys), abrogates β1 cell adhesion and channel modulation ([PMID:31465153]). No recurrent or population-specific founder alleles have been described in DEE cases.

Functional studies in Scn1b knockout mice reveal increased neuronal firing and spontaneous seizures, mirroring human pathology ([PMID:19710327]). In vitro assays of human β1B p.G257R and p.R125C variants demonstrate intracellular retention and loss of modulatory activity on Nav1.1 and Nav1.3 channels ([PMID:21994374]). These data support loss of β1-mediated sodium current regulation as the mechanism of disease.

No studies to date have refuted the association between biallelic SCN1B variants and DEE. The combined genetic and experimental evidence meets ClinGen criteria for a Moderate gene-disease relationship, with both segregation and functional concordance.

Key take-home: Biallelic SCN1B loss-of-function variants cause autosomal recessive developmental and epileptic encephalopathy, and early genetic diagnosis can guide precision therapy including consideration of fenfluramine.

References

• Children (Basel, Switzerland) • 2022 • SCN1B Genetic Variants: A Review of the Spectrum of Clinical Phenotypes and a Report of Early Myoclonic Encephalopathy. PMID:36291443
• American Journal of Medical Genetics Part A • 2019 • Developmental and epileptic encephalopathy in two siblings with a novel, homozygous missense variant in SCN1B. PMID:31465153
• The Journal of Neuroscience • 2009 • A functional null mutation of SCN1B in a patient with Dravet syndrome. PMID:19710327
• The Journal of Neuroscience • 2011 • Voltage-gated Na⁺ channel β1B: a secreted cell adhesion molecule involved in human epilepsy. PMID:21994374

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