Vanishing white matter disease (VWM) is a severe leukodystrophy of the central nervous system caused by mutations in subunits of the eukaryotic initiation factor 2B complex (eIF2B). Current models only partially recapitulate key disease features, and pathophysiology is poorly understood. Through development and validation of zebrafish (Danio rerio) models of VWM, we demonstrate that zebrafish eif2b mutants phenocopy VWM, including impaired somatic growth, early lethality, effects on myelination, loss of oligodendrocyte precursor cells, increased apoptosis in the CNS, and impaired motor swimming behavior. Expression of human EIF2B2 in the zebrafish eif2b2 mutant rescues lethality and CNS apoptosis, demonstrating conservation of function between zebrafish and human. In the mutants, intron 12 retention leads to expression of a truncated eif2b5 transcript. Expression of the truncated eif2b5 in wild-type larva impairs motor behavior and activates the ISR, suggesting that a feed-forward mechanism in VWM is a significant component of disease pathophysiology.

Background-Leukodystrophies are genetic diseases affecting the white matter and leading to early death. Our objective was to determine leukodystrophy incidence, using genomics sequencing databases allele frequencies of disease-causing variants.Methods-From 49 genes, representing the standardly defined group of leukodystrophies, we identified potential disease-causing variants from publications in the Human Genetic Mutation Database and from predictions in the Genome Aggregation Database (gnomAD). Allele frequencies were estimated from gnomAD. Allele frequencies for each gene were summed to generate a super allele frequency (SAF) and we used the Hardy-Weinberg equation to calculate overall expected live birth incidence associated with the gene in question.Results-We identified 4,564 pathogenic variants for 25 discrete leukodystrophies. The largest effect was from GALC variants (Krabbe disease), which had a predicted incidence of 1 in 12,080 live births, 8.3 times higher than published estimates. The second most frequently predicted leukodystrophy were the POLIII-related disorders, which had an incidence of 1:26,160. Overall, we found a leukodystrophy incidence of 1 in 4,733 live births, significantly higher than previous estimates.

Background: The genes responsible for genetic white matter disorders (GWMD; leukodystrophies and leukoencephalopathies) are incompletely known. Our goal was to revise the list of genes considered to cause GWMD. We considered a GWMD to consist of any genetic disease causing T2 signal white matter changes in magnetic resonance images. Methods and Results: Using a systematic review of PubMed, Google, published literature reviews, and commercial gene panels, we identified 399 unique genes meeting the GWMD definition. Of this, 87 (22%) genes were hypomyelinating. Only 3 genes had contrast enhancement on magnetic resonance imaging (MRI): ABCD1, GFAP, and UNC13D. Conclusions: A significantly greater number of genes than previously recognized, 399, are associated with white matter signal changes on T2 MRI. This expansion of GWMD genes can be useful in analysis and interpretation of next-generation sequencing results for GWMD diagnosis, and for understanding shared pathophysiological mechanisms of GWMDs.

31Vanishing White Matter disease (VWM) is a severe leukodystrophy of the central nervous 32 system caused by mutations in subunits of the eukaryotic initiation factor 2B complex (eIF2B). 33 Current models only partially recapitulate key disease features, and pathophysiology is poorly 34 understood. Through development and validation of zebrafish (Danio rerio) models of VWM, 35 we demonstrate that zebrafish eif2b mutants phenocopy VWM, including impaired somatic 36 growth, early lethality, impaired myelination, loss of oligodendrocyte precursor cells, increased 37 apoptosis in the CNS, and impaired motor swimming behavior. Expression of human EIF2B2 in 38 the zebrafish eif2b2 mutant rescues lethality and CNS apoptosis, demonstrating conservation of 39 function between zebrafish and human. In the mutants, intron 12 retention leads to expression of 40 a truncated eif2b5 transcript. Expression of the truncated eif2b5 in wild-type larva impairs motor 41 behavior and activates the ISR, suggesting that a feed-forward mechanism in VWM is a 42 significant component of disease pathophysiology. 43 44 45 46

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