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

• Published in: Cold Spring Harbor molecular case studies Vol. 4; no. 3; p. a002360
• Main Authors: Bodian, Dale L., Schreiber, John M., Vilboux, Thierry, Khromykh, Alina, Hauser, Natalie S.
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.06.2018
• Subjects: Age; Age of Onset; Alleles; Alternative Splicing; Biomarkers; Brain; Chromosome Mapping; Convulsions & seizures; Diagnostic systems; DNA Mutational Analysis; Electroencephalography; Encephalopathy; Epilepsy; Epileptic Syndromes - diagnosis; Epileptic Syndromes - genetics; Exons; Gene Frequency; Gene sequencing; Genetic screening; Genomes; Humans; Infant, Newborn; Male; Mutation; Pedigree; Phenotype; Protein-Serine-Threonine Kinases - genetics; Research Reports; Seizures; Seizures - diagnosis; Seizures - genetics; Sequence Deletion; Spasms, Infantile - diagnosis; Spasms, Infantile - genetics; Transcription; Whole Genome Sequencing; infantile spasms; generalized tonic seizures
• ISSN: 2373-2865; 2373-2873; 2373-2873
• DOI: 10.1101/mcs.a002360

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.