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Identification of a Missense Variant in the Eif2b3 Gene Causing Vanishing White Matter Disease With Antenatal-Onset But Mild Symptoms and Long-Term Survival Publisher Pubmed



Khorrami M1 ; Khorram E1 ; Yaghini O2 ; Rezaei M3 ; Hejazifar A4 ; Iravani O5 ; Yazdani V6 ; Riahinezhad M7 ; Kheirollahi M1
Authors
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Authors Affiliations
  1. 1. Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
  2. 2. Child Growth and Development Research Center, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
  3. 3. Department of Biology, Faculty of Science, Yazd University, Yazd, Iran
  4. 4. Department of Biology, School of Sciences, The University of Isfahan, Isfahan, Iran
  5. 5. Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran
  6. 6. Department of Biology, Islamic Azad University, East Tehran Branch, Tehran, Iran
  7. 7. Department of Radiology, Isfahan University of Medical Sciences, Isfahan, Iran

Source: Journal of Molecular Neuroscience Published:2021


Abstract

Vanishing white matter disease (VWM) is a rare autosomal recessive leukodystrophy caused by a mutation in any of the five gene encoding subunits of the translation initiation factors eIF2B1 to eIF2B5. Whole-exome sequencing was performed on a 7-year-old boy with prenatal symptoms, including intrauterine-growth retardation, decreased movements, and oligohydramnios as well as mild intellectual disability, optic atrophy, macrocephaly, mild ataxia, and white matter lesions after birth. Analysis of WES data revealed a homozygous missense variant, c.C590T (p.Thr197Met) in the EIF2B3 gene (NM_0203650). The candidate variant was confirmed by Sanger sequencing and found to co-segregate with disease in family members. Pathogenicity analysis, 3D protein modeling, and stability assessment showed the deleterious effects of this nucleotide change. Previous studies suggest a direct relationship between the onset of symptoms and the progression rate and severity of the disease. All described cases of EIF2B deficiency with antenatal-onset led prenatal death; if they were born, they experienced clinical exacerbation, seizure, severe encephalopathy, and consequent infantile death (< 1 year). The patient of this study had never had seizure, which could be a potential explanation for the observed mild clinical picture, chronic state, and long-term survival until the age of seven. This study reported the first VWM due to EIF2B gene deficiency with antenatal-onset but mild symptoms and long-term survival. The result of this study showed that stressor factors, particularly seizure, could have a substantial role in poor prognosis and early neonatal death. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.
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