Abstract
Vanishing of white matter (VWM) is a hereditary heterogeneous brain disorder that most often affects children. However, the onset of the disease varies from childhood to adulthood. VWM is caused by mutations in one of the five genes encoding subunits of the eukaryotic initiation factor eIF2B. In the current study, we aimed to determine the genetic cause of VWM in a large consanguineous Iranian family with three affected members. Next-generation sequencing was conducted on the proband to determine the underlying cause of VWM. The identified variant was validated by PCR-Sanger sequencing in the patient and was also segregated in his parents and two other affected members of the pedigree. The potential functional effects of this mutation within EIF2B5 were predicted by in silico analysis. We have also reviewed all EIF2B5 disease-causing variants and available clinical features of each patient reported in HGMD Professional 2022.2. A novel homozygous variant c.746T>G [p.Ile249Ser] was detected in EIF2B5 which was co-segregated with the disease in all affected family members in an autosomal recessive manner. All employed in silico prediction tools and 3D structure analysis for the novel mutation also supported the pathogenicity of this variant. Our study not only expanded the spectrum of the pathogenic variants in EIF2B5 but also presented a literature review on EIF2B5-related conditions that provide a comprehensive picture of the genetic nature of this gene and phenotypic variability in patients.
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Our team would like to thank the patients and families for their participation in the study.
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PN, participated in sample/data collection, and molecular experiments, reviewed the literature and drafted the work; MA contributed to the conception and design of the work, bioinformatics analysis, figures and tables design, reviewed the literature and drafted the work; AK participated in WES data analysis, drafted the work, and reviewed the manuscript; MB participated in the analysis of the MRI scan; YE, ZG, SRT and MT contributed extensively to the interpretation of data; SH, involved in molecular experiments; MK supervision of the project, reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors read and approved the final manuscript.
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Corresponding editor: S. Ganesh
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Nourmohammadi, P., Asadollahi, M., Karamzade, A. et al. A novel missense variant in EIF2B5 identified in a consanguineous Iranian family with vanishing white matter disease and a brief review of the literature. J Genet 102, 39 (2023). https://doi.org/10.1007/s12041-023-01436-8
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DOI: https://doi.org/10.1007/s12041-023-01436-8