Figure 2. Detection of a heterozygous de novo nonsense mutation in CLCN1 in a proband with childhood-onset idiopathic generalized epilepsy including cortical spike-wave absence seizures and a history of writer's cramp.

(A) Schematic diagram of a single α subunit of the ClC-1 channel protein showing the location of the novel C-terminal truncation mutation (R976X) identified in a single proband in the study cohort. (B) PCR amplification of the final coding exon (exon 23) of CLCN1 in the trio yielded a 550 bp product (arrow) used as a template in a Sanger sequencing reaction. (C) Sequence chromatograms for the trio compared to the NCBI reference gene (NM_000083) indicating the heterozygous base pair substitution encoding a premature stop codon in the proband. Neither parent has the mutation, indicating that it is de novo, resulting from a spontaneous C to T transition in the proband. (D) A multi-lead EEG recording from the proband during a typical absence seizure 20 seconds in duration exhibiting 3-Hz generalized spike-and-wave complexes.