Document Type


Publication Date



DOI: 10.3389/fneur.2023.1148377; PMCID: PMC10108901


Introduction: Rare neurodevelopmental disorders, including inherited white matter disorders or leukodystrophies, often present a diagnostic challenge on a genetic level given the large number of causal genes associated with a range of disease subtypes. This study aims to demonstrate the challenges and lessons learned in the genetic investigations of leukodystrophies through presentation of a series of cases solved using exome or genome sequencing.

Methods: Each of the six patients had a leukodystrophy associated with hypomyelination or delayed myelination on MRI, and inconclusive clinical diagnostic genetic testing results. We performed next generation sequencing (case-based exome or genome sequencing) to further investigate the genetic cause of disease.

Results: Following different lines of investigation, molecular diagnoses were obtained for each case, with patients harboring pathogenic variants in a range of genes including TMEM106B, GJA1, AGA, POLR3A, and TUBB4A. We describe the lessons learned in reaching the genetic diagnosis, including the importance of (a) utilizing proper multi-gene panels in clinical testing, (b) assessing the reliability of biochemical assays in supporting diagnoses, and (c) understanding the limitations of exome sequencing methods in regard to CNV detection and region coverage in GC-rich areas.

Discussion: This study illustrates the importance of applying a collaborative diagnostic approach by combining detailed phenotyping data and metabolic results from the clinical environment with advanced next generation sequencing analysis techniques from the research environment to increase the diagnostic yield in patients with genetically unresolved leukodystrophies.

Journal Title

Front Neurol



First Page


Last Page



genetic diagnosis; hypomyelination; leukodystrophy; medical genetics; neurogenetics; next generation sequencing (NGS); pediatric neurology; white matter disorders


Grant support

This research study was supported by project grants from the Canadian Institutes of Health Research (377869 and 426534). The work from IT and TP were made possible by the generous gifts to Children's Mercy Research Institute and Genomic Answers for Kids Program at Children's Mercy Kansas City. GB has received the Clinical Research Scholar Junior 1 Award from the Fonds de Recherche du Quebec-Santé (FRQS) (2012–2016), the New Investigator Salary Award from the Canadian Institutes of Health Research (2017–2022), and the Clinical Research Scholar Senior award from the FRQS (2022–2025). SP has been supported by the FRQS Doctoral Scholarship, the Fondation du Grand défi Pierre Lavoie Doctoral Scholarship, the McGill Faculty of Medicine F.S.B. Miller Fellowship, and the Research Institute of the McGill University Health Center Desjardins Studentship in Child Health Research. MM-R was supported by the Vanier Canada Graduate Scholarship and the McGill University Faculty of Medicine. TP holds the Dee Lyons/Missouri Endowed Chair in Pediatric Genomic Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Publisher's Link: