Postmortem Whole Exome Sequencing Identifies Novel EIF2B3 Mutation With Prenatal Phenotype in 2 Siblings

Area of Science:

• Genetics
• Neurology
• Pediatrics

Background:

• Vanishing white matter disease (VWW) is a severe, early-onset leukodystrophy.
• Prenatal diagnosis of VWW is challenging due to nonspecific imaging findings.

Observation:

• Two male siblings presented with abnormal prenatal neuroimaging and rapid, fatal neurological decline.
• Neuropathology revealed profound myelin deficiency in the brain but spared peripheral nerves.

Findings:

• Whole exome sequencing identified a novel homozygous mutation in the EIF2B3 gene (c.97A>G [p.Lys33Glu]) in both affected siblings.
• Both parents were confirmed as heterozygous carriers for the identified mutation.

Implications:

• This case expands the known prenatal phenotype of eIF2b-related disorders.
• Genomic sequencing significantly impacted diagnosis and guided reproductive decisions, including successful preimplantation genetic screening for a healthy sibling.