Mutation in an alternative transcript of CDKL5 in a boy with early-onset seizures

Abstract

Infantile-onset epilepsies are a set of severe, heterogeneous disorders for which clinical genetic testing yields causative mutations in ∼20%-50% of affected individuals. We report the case of a boy presenting with intractable seizures at 2 wk of age, for whom gene panel testing was unrevealing. Research-based whole-genome sequencing of the proband and four unaffected family members identified a de novo mutation, NM_001323289.1:c.2828_2829delGA in CDKL5, a gene associated with X-linked early infantile epileptic encephalopathy 2. CDKL5 has multiple alternative transcripts, and the mutation lies in an exon in the brain-expressed forms. The mutation was undetected by gene panel sequencing because of its intronic location in the CDKL5 transcript typically used to define the exons of this gene for clinical exon-based tests (NM_003159). This is the first report of a patient with a mutation in an alternative transcript of CDKL5 This finding suggests that incorporating alternative transcripts into the design and variant interpretation of exon-based tests, including gene panel and exome sequencing, could improve the diagnostic yield.

Keywords: generalized tonic seizures; infantile spasms.

Figure 1.

Family pedigree and Sanger sequencing of the region of the CDKL5 variant. The 2-bp deletion NM_001323289.1:c.2828_2829delGA on Chromosome X was detected in the proband (black square) in the haploid state but not in the four unaffected family members.

Figure 2.

Genomic region of the CDKL5 variant. Predicted coding sequence in this region from transcripts NM_003159 and NM_00132389 are represented by thick black bars, UTRs by thin bars, and intronic sequence by lines with arrowheads indicating the direction of transcription (Kent et al. 2002). The patient's mutation, labeled delAG, is indicated in red. ClinVar (Landrum et al. 2016) variants annotated as pathogenic or likely pathogenic are displayed. “gnomAD lof” tracks show variants from gnomAD (Lek et al. 2016) predicted to be stop-gain, frameshift, or splicing variants for NM_003159 or NM_00132389.