Abstract
Investigating novel genetic variants involved in intellectual disability (ID) development is essential. X-linked intellectual disability (XLID) accounts for over 10% of all cases of ID in males. XLID genes are involved in many cellular pathways and processes. Some of them are not specific to the development and functioning of the neural system. The implementation of exome sequencing simplifies the search for novel variants, especially those less expected. Here, we describe a nonsense variant of the XLID gene, WDR13. The mutation c.757C>T (p.Arg253Ter) was uncovered by X-chromosome exome sequencing in males with a familial form of intellectual disability. Quantitative PCR (qPCR) analysis showed that variant c.757C>T caused a significant decrease in WDR13 expression in the patient's fibroblast. Moreover, it dysregulated other genes linked to intellectual disability, such as FMR1, SYN1, CAMK2A, and THOC2. The obtained results indicate the pathogenic nature of the detected variant and suggest that the WDR13 gene interacts with other genes essential for the functioning of the nervous system, especially the synaptic plasticity process.
Highlights
Intellectual disability (ID) is a heterogeneous group of rare diseases characterized by deficits in intellectual and adaptive functioning of varying severity
Additional analyses showed that the lack of the WDR13 gene in the patient's fibroblast caused dysregulation of the expression of several neural genes involved in the development of ID, including FMR1
It is necessary to conduct detailed research that would allow for a better understanding of the process of intellectual disability development related to the WDR13 gene
Summary
Intellectual disability (ID) is a heterogeneous group of rare diseases characterized by deficits in intellectual and adaptive functioning of varying severity. The CAMK2A gene is required for hippocampal long-term potentiation (LTP) and spatial learning Pathogenic variants of this gene are a well-known cause of both recessive and dominant forms of intellectual disability (OMIM#:618095, 617798). Little is known about the role of the WDR13 protein in the development of intellectual disability. Revealed intragenic deletion of the WDR13 gene in a family with suspected XLID [5] Another group found microduplication encompassing the WDR13 in an 11-year-old boy with hyperactivity, learning, and visual–spatial difficulties [6]. All reported variants are likely pathogenic according to in silico analysis results, but there is no evidence of the brain-specific function of the WDR13 in these patients. Our study found a loss-of-function variant of the WDR13 gene in a male patient with an intellectual disability whose family history indicates X-linked inheritance. Additional analyses showed that the lack of the WDR13 gene in the patient's fibroblast caused dysregulation of the expression of several neural genes involved in the development of ID, including FMR1
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