Two Novel Variants Affecting CDKL5 Transcript Associated with Epileptic Encephalopathy
Language English Country United States Media print-electronic
Document type Case Reports, Journal Article
- Keywords
- CDKL5 gene, early onset seizures, infantile epileptic encephalopathy 2, massively parallel sequencing, splice site variant,
- MeSH
- Epilepsy genetics MeSH
- Epileptic Syndromes MeSH
- Exons MeSH
- Genetic Variation genetics MeSH
- Spasms, Infantile genetics MeSH
- Humans MeSH
- Mutation MeSH
- Child, Preschool MeSH
- Protein Serine-Threonine Kinases genetics metabolism MeSH
- Rett Syndrome genetics MeSH
- High-Throughput Nucleotide Sequencing MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Names of Substances
- CDKL5 protein, human MeSH Browser
- Protein Serine-Threonine Kinases MeSH
BACKGROUND: Variants in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been reported as being etiologically associated with early infantile epileptic encephalopathy type 2 (EIEE2). We report on two patients, a boy and a girl, with EIEE2 that present with early onset epilepsy, hypotonia, severe intellectual disability, and poor eye contact. METHODS: Massively parallel sequencing (MPS) of a custom-designed gene panel for epilepsy and epileptic encephalopathy containing 112 epilepsy-related genes was performed. Sanger sequencing was used to confirm the novel variants. For confirmation of the functional consequence of an intronic CDKL5 variant in patient 2, an RNA study was done. RESULTS: DNA sequencing revealed de novo variants in CDKL5, a c.2578C>T (p. Gln860*) present in a hemizygous state in a 3-year-old boy, and a potential splice site variant c.463+5G>A in heterozygous state in a 5-year-old girl. Multiple in silico splicing algorithms predicted a highly reduced splice site score for c.463+5G>A. A subsequent mRNA study confirmed an aberrant shorter transcript lacking exon 7. CONCLUSIONS: Our data confirmed that variants in the CDKL5 are associated with EIEE2. There is credible evidence that the novel identified variants are pathogenic and, therefore, are likely the cause of the disease in the presented patients. In one of the patients a stop codon variant is predicted to produce a truncated protein, and in the other patient an intronic variant results in aberrant splicing.
References provided by Crossref.org
