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Diagnostic Odyssey: Investigating the Role of a Mutation in the CUL4B Gene and its Effect on the CUL4B Protein Complex in a Patient with Seizures and Developmental Delay


For many patients with complex diseases the time from onset of symptoms to diagnosis may involve many years. If a diagnosis can be reached, it often comes at great financial and emotional cost. With the advent of sequencing technologies, the ability to identify gene variants has increased exponentially. Interpreting these findings, however, remains challenging. The purpose of this study was to analyze a mutation in the CUL4B gene revealed by whole exome sequencing (WES) in a patient with seizures and developmental delay. Recognizing that complex disease may involve the interaction of many genes and their protein products, an analysis of variants in selected CUL4B associated proteins and CUL4A was also undertaken with the ultimate goal of determining their potential clinical relevancy.

WES was performed by Ambry Genetics and mRNA studies were performed by University of California CLIA laboratory MitoMed. WES identified a variant in CUL4B located on the X chromosome. Analysis revealed a splice site mutation resulting in skipping of exon 14 or inclusion of intron 14. Examination of the biological structure indicated that in either case no functional protein would be found. Fifteen intronic variants and one synonymous exonic variant were identified in CUL4B related genes. Fourteen intronic variants in CUL4A were also identified. Current understanding of these types of variants suggests they would not be contributory, however further study is required. Taken together, these results contribute to the growing body of evidence that mutations in the CUL4B gene may be causal in cases of X linked intellectual disability.

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