Genetic analysis of leukodystrophies in children: towards improved diagnostic yield

The formation of the myelin sheath in the central nervous system is carried out by oligodendrocytes, and leukodystrophies develop when myelination by oligodendrocytes is impaired. It has been found that the activity of the neurons undergoing myelination is also necessary for complete myelination, meaning that not only abnormalities in oligodendrocytes but also abnormalities in neurons can lead to defective myelination. Many genes involved in leukodystrophy in children have been identified, and comprehensive genetic analysis has been proven useful for genetic diagnosis. However, target panel sequencing, exome sequencing targeting almost all exons, and genome sequencing does not identify the genetic cause in substantial proportion of patients, making it essential to advance research targeting these unresolved cases. Transcriptome analysis has been reported to improve diagnostic rates in individuals with suspected Mendelian conditions, by confirming aberrant splicing caused by candidate DNA variants or by revealing candidate loci through detecting abnormalities in RNA transcription. Because transcription has a tissue specificity, selection of tissues from which RNA extract is of importance. In this mini-review, we first briefly review genetics of leukodystrophies in children along with methodology of genetic analysis, and discuss utility of urine-derived cells for transcriptome analysis of leukodystrophy in children.