Epilepsy: Benign Familial Neonatal Seizures Type 2 via the KCNQ3 Gene

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. Seizures are generally brief, lasting one to two minutes. Seizure types include tonic or apneic episodes, focal clonic activity or autonomic changes. In classic BFNS cases, psychomotor development is not affected. BFNS has a similar clinical presentation to benign familial neonatal-infantile seizures (BFNIS) and benign familial infantile seizures (BFIS) and is largely distinguished from these disorders by an earlier age of onset (Zara et al. 2013). In general, KCNQ3 pathogenic variants cause typical BFNS, however, they can be also found in patients with more severe phenotypes including intellectual disability (Miceli et al 2015).

Benign familial neonatal seizures are inherited in an autosomal dominant manner and can be caused by pathogenic variants in KCNQ3 (Wilmshurst et al 2015; Ottman et al 2010). The reported KCNQ3 pathogenic variants are missense, as well as a large deletion encompassing the KCNQ3 locus (Grinton et al. 2015; Allen et al. 2014). The KCNQ3 protein contains six trans-membrane domains and the pore region. BFNS-associated pathogenic variants in KCNQ3 usually affect the pore region of the protein (Charlier et al 1989). The penetrance of KCNQ3 pathogenic variants can be incomplete, which may be due to unrecognized brief manifestation of neuronal seizures.

KCNQ3 is potassium voltage-gated channel, subfamily Q, member 3. It encodes the alpha subunit of the voltage-gated potassium ion channel (Charlier et al 1989). The gene is highly expressed in neurons of the brain. The KCNQ3 alpha subunits co-assemble with alpha subunits of KCNQ2 to form a heteromeric functional potassium channel that transmits a M-current, a slowly activating, non-inactivating potassium conductance that stabilizes membrane potential and inhibits excessive neuronal activity (Bellini et al. 2014). Slight loss of KCNQ2/3 channel activity leads to a hyperexcitability of certain neurons and thereby causes seizures (Jentsch et al 2000).

In a large cohort study of benign familial neonatal seizures, a molecular cause in KCNQ2, KCNQ3 or SCN2A was identified in 91% of cases (Grinton et al. 2015). Compared to KCNQ2, pathogenic variants in KCNQ3 are found to be a rare cause in cases of benign familial neonatal seizures (Allen et al. 2014; Grinton et al. 2015).

This test provides full coverage of all coding exons of the KCNQ3 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.