Generalized Epilepsy with Febrile Seizures Plus and Dravet syndrome via the SCN1B Gene

Generalized epilepsy with febrile seizures plus (GEFS+; OMIM:604233) is a familial epilepsy syndrome characterized by  febrile seizures. GEFS+ patients usually present with fever induced seizures between the ages of 6 months and 6 years. 'Plus' refers to the persistence of seizures into adolescence when patients may also experience myoclonic, absence or focal seizures. Patients with GEFS+ usually have at least two family members with GEFS+ spectrum phenotypes and seizure-type heterogeneity is typical among family members (Scheffer et al. Brain Dev 31(5):394-400, 2009).

Dravet syndrome (DS; OMIM: 607208) is one of a group of early infantile epileptic encephalopathies (EIEE). DS is characterized by the onset of seizures within the first year of life in children with previously normal psychomotor development. Early seizures can be clonic or clonic-tonic and are usually brought on by fever. DS is characterized by the presence of multiple seizure types within a patient, including: myoclonic jerks, absence seizures, focal seizures, photosensitive seizures and prolonged seizures resulting in status epilepticus (Akiyama et al. Acta Med. Okayama 66(5):369-376, 2012). Seizures observed in DS are resistant to treatment with anti-epileptic drugs. DS patients suffer severe cognitive and motor impairments that persist throughout their lives.

GEFS+ is inherited in an autosomal dominant manner with incomplete penetrance. Mutations in SCN1B have been identified in a small percent of GEFS+ families and show ~63% penetrance (Audenaert et al. Neurology 61(6):854-856, 2003). GEFS+ cases can also be sporadic with no family history.

Recessive mutations in SCN1B have also been reported in rare cases of Dravet syndrome (Patino et al. J Neurosci 29(34):10764-10778, 2009; Ogiwara et al. Epilepsia. 53(12):e200-e203, 2012).

SCN1B encodes a beta subunit of the voltage-gated sodium channel. SCN1B has been shown to modulate the excitability of sodium channels, mediate cell-cell adhesions and direct neurite outgrowth- all of which may contribute to the epilepsy phenotypes associated with SCN1B mutations (Patino et al., 2009).

SCN1B mutations are found in 1-2% of patients with idiopathic childhood epilepsies and ~4% of cases where febrile seizures are a key clinical feature (Orrico et al. Clin Genet 75(6):579-581; Scheffer et al. Brain 130(Pt 1):100-109, 2007).

Thus far, no gross deletions or duplications have been reported in SCN1B (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the SCN1B gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.