Background: Benign familial neonatal seizures (BFNS) is most often caused by mutations in the voltage-gated potassium channel subunit gene KCNQ2. More than 60 mutations have been described in BFNS families, approximately half of which lead to protein truncation. We hypothesized that the deletion or duplication of one or more exons of KCNQ2 could cause BFNS in cases without coding or splicing mutations.
Materials and Methods: We used multiplex ligation-dependent probe amplification (MLPA) to test a group of 21 unrelated patients with clinical features consistent with either BFNS, benign familial neonatal-infantile seizures (BFNIS) or sporadic neonatal seizures, for exonic deletions and duplications.
Results: Three deletions and one duplication mutation were identified in four familial cases and cascade testing of their available family members showed that the mutations segregated with the phenotype in each family. The junction fragment for one of the deletions was PCR amplified and sequenced to characterize the breakpoint and verify that deletion occurred.
Conclusions: Submicroscopic deletions or duplications of KCNQ2 are seen in a significant proportion of BFNS families – four of nine cases (44%) previously testing negative for coding or splice site mutation by sequencing KCNQ2 and KCNQ3. MLPA is an efficient second tier testing strategy for KCNQ2 to identify pathogenic intragenic mutations not detectable by conventional DNA sequencing methods.
- Neonatal seizures
- Potassium channel
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