Early Infantile Epileptic Encephalopathy and Benign Familial Neonatal Seizures via the KCNQ2 Gene

Early infantile epileptic encephalopathy-7 (EIEE7) is a seizure disorder characterized by infantile onset of clonic-tonic seizures and moderate to profound intellectual disability. Symptoms of EIEE7 include: hypotonia, onset of refractory seizures during infancy, burst suppression EEG readings that evolve into to multifocal eplileptiform activity and delayed psychomotor development (Kato et al. 2013). Symptoms of EIEE7 largely overlap with those of Ohtahara Syndrome (OMIM: 308350). Benign familial neonatal seizures (BFNS) are clusters of seizures that occur within the first week of life. Normal development is seen prior to seizure onset and seizures spontaneously remit by 12 months of age (Zara et al. 2013). In classic BFNS cases, psychomotor development is not affected, but some BFNS cases evolve into more severe seizure disorders such as EIEE7. BFNS has a similar clinical presentation to benign familial neonatal-infantile seizures (BFNIS; OMIM:121201) and benign familial infantile seizures (BFIS; OMIM:605751) and is largely distinguished from these disorders by an earlier age of onset (Zara et al. 2013).

EIEE7 is caused by heterozygous missense mutations in the KCNQ2 gene. Most cases of EIEE7 are sporadic, resulting from de novo mutations in KCNQ2. BFNS is inherited in an autosomal dominant manner and can be caused by missense and nonsense mutations in KCNQ2 as well as deletions or duplications of the KCNQ2 locus (Heron et al. 2007). KCNQ2 encodes a subunit of the neuronally expressed voltage-gated potassium (K+) ion channel. These K+ channels are responsible for dampening membrane sensitivity of surrounding channels. Loss of K+ channels is believed to result in neuronal hyperexcitability. BFNS is associated with deletions or loss of function mutations in KCNQ2, suggesting that KCNQ2 haploinsufficiency underlies the BFNS phenotype. In contrast, EIEE7 is caused largely by missense mutations in KCNQ2, it is believed that these mutations act in a dominant-negative fashion. Potassium channels are tetramers, requiring the assembly of four functional subunits. Studies in mice have shown that missense mutations in critical domains of KCNQ2 can assemble with wild-type subunits and impede their function, resulting in a more severe phenotype than simple haploinsufficiency of KCNQ2 (Peters et al. 2004).

KCNQ2 mutations have been reported in ~20% of Ohtahara-like EIEE cases in which mutations in STXBP1 or ARX (in males) were previously excluded (Milh et al. 2013; Kato et al. 2013). KCNQ2 deletions and single nucleotide variants were reported in 88% (7 of 8) of families diagnosed with BFNS and 67% (6 of 9) of families diagnosed with BFNIS (Zara et al. 2013).

This test provides full coverage of all coding exons of the KCNQ2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.