Dravet Syndrome and Generalized Epilepsy with Febrile Seizures Plus via the SCN1A Gene

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. Early EEGs of DS patients reveal no electroclinical abnormalities, but a generalized spike wave pattern is seen as the disease progresses. DS is characterized by the presence of multiple seizure types within patients, including: myoclonic jerks, absence seizures, focal seizures, photosensitive seizures and prolonged seizures resulting in status epilepticus (Akiyama et al. 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.

Dravet syndrome is an autosomal dominant condition caused by loss of function mutations in SCN1A, which can include missense, nonsense and splice site mutations as well as insertions or deletions that disrupt the reading frame. The majority (94%) of mutations in SCN1A associated with DS arise de novo (Vadlamudi et al. 2010). Thus, DS cases are sporadic, occurring in individuals with no family history of Dravet syndrome. Rare cases of inherited DS are seen in situations where the proband's parent was mosaic for the causative SCN1A variant.

Mutations in SCN1A can also cause Generalized epilepsy with febrile seizures plus (GEFS+, OMIM:604403). GEFS+ is a milder infantile seizure disorder characterized by febrile seizures. GEFS+ is associated with missense mutations in SCN1A (Guerrini et al. 2010). GEFS+ cases can be sporadic or inherited in an autosomal dominant manner.

SCN1A encodes a neuronally expressed alpha subunit of the voltage-gated sodium channel. Sodium channels are excitatory and propagate action potentials in neurons. Epilepsy disorders are characterized by hyperexcitability of neurons. SCN1A-containing sodium channels normally activate a set of inhibitory neurons in the neocortex and hypothalamus. These inhibitory neurons release a neurotransmitter, GABA, which is important for balancing excitation and inhibition in the brain. It is proposed that mutations in SCN1A relieve GABAergic inhibition in the neocortex and hypothalamus, resulting in neuronal hyperactivity and epilepsy (Yu et al. 2006; Catterall et al. 2010).

Causative variants in SCN1A have been reported in 79% (52 of 66) of patients with Dravet syndrome (Harkin et al. 2007). Causative SCN1A variants are detected in ~10% of patients with GEFS+ (Scheffer et al. 2009).

This test provides full coverage of all coding exons of the SCN1A gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.