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.

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. Allele frequencies were estimated from Genome Aggregation Database. Allele frequencies for each gene were summed to generate a super allele frequency and we used the Hardy-Weinberg equation to calculate overall expected live birth incidence associated with the gene in question.

We identified 4564 pathogenic variants for 25 discrete leukodystrophies. The largest effect was from GALC variants (Krabbe disease), which had a predicted incidence of one in 12,080 live births, 8.3 times higher than published estimates. The second most frequently predicted leukodystrophy was the RNA polymerase III–related disorders, which had an incidence of 1:26,160. Overall, we found a leukodystrophy incidence of 1 in 4733 live births, significantly higher than previous estimates.

Our data are consistent with a significant underdiagnosis of leukodystrophy patients. An intriguing additional consideration is that there may be genetic modifiers that lead to weaker, absent, or adult-onset disease phenotypes.