Early Infantile Epileptic Encephalopathy via the KCNA2 Gene

Early infantile epileptic encephalopathy 32 is characterized by febrile or afebrile focal seizures with mild to moderate intellectual disability, delayed speech development, ataxia, tremor, and myoclonus. Seizure types can be hemiclonic, myoclonic, myoclonic-atonic, focal dyscognitive, generalized tonic-clonic, or absence. Patients have normal early development until the onset of seizures between 5 and 17 months of age. After a period of several years with frequent seizures, seizures significantly reduce and patients may even become seizure-free. The seizures can be significantly decreased by medication in some patients. EEG findings are variable, and include multifocal sharp waves, sharp slow waves, polyspikes, or generalized spike waves. MRI generally shows normal findings (Syrbe et al. 2015).

Early infantile epileptic encephalopathy 32 is inherited in an autosomal dominant manner and is caused by pathogenic variants in KCNA2. KCNA2 encodes voltage-gated potassium channel, shaker-related subfamily, member 2. The reported KCNA2 pathogenic variants are missense, as well as one large deletion encompassing the KCNA2 locus (Syrbe et al. 2015; Lal et al. 2015). The vast majority of pathogenic variants occurred de novo (Syrbe et al. 2015; Hundallah et al. 2016). Patients with gain-of-function pathogenic variants have a more severe phenotype and have frequent seizures. In contrast, patients with loss-of-function pathogenic variants have late-onset seizures, and become seizure-free in childhood (Kearney 2015).

De novo pathogenic variants in KCNA2 cause mild to severe epileptic encephalopathy in roughly 1.7% of cases across different cohorts (Syrbe et al 2015).

This test provides full coverage of all coding exons of the KCNA2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.