Solving inherited white matter disorder etiologies in the neurology clinic: Challenges and lessons learned using next-generation sequencing

Stefanie Perrier; Kether Guerrero; Luan T Tran; Mackenzie A Michell-Robinson; Geneviève Legault; Bernard Brais; Michel Sylvain; James Dorman; Michelle Demos; Wolfgang Köhler; Tomi Pastinen; Isabelle Thiffault; Geneviève Bernard

doi:10.3389/fneur.2023.1148377

Solving inherited white matter disorder etiologies in the neurology clinic: Challenges and lessons learned using next-generation sequencing

Front Neurol. 2023 Apr 3:14:1148377. doi: 10.3389/fneur.2023.1148377. eCollection 2023.

Authors

Stefanie Perrier^{1

2}, Kether Guerrero^{1

2}, Luan T Tran^{1

2}, Mackenzie A Michell-Robinson^{1

2}, Geneviève Legault^{1

2

3}, Bernard Brais^{1

4

5}, Michel Sylvain⁶, James Dorman^{7

8}, Michelle Demos⁹, Wolfgang Köhler¹⁰, Tomi Pastinen^{11

12}, Isabelle Thiffault^{11

12

13}, Geneviève Bernard^{1

2

3

5

14}

Affiliations

¹ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
² Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
³ Department of Pediatrics, McGill University, Montreal, QC, Canada.
⁴ Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
⁵ Department of Human Genetics, McGill University, Montreal, QC, Canada.
⁶ Division of Pediatric Neurology, Centre Mère-Enfant Soleil du CHU de Québec - Université Laval, Québec City, QC, Canada.
⁷ John H. Stroger Jr. Hospital of Cook County, Chicago, IL, United States.
⁸ Department of Neurological Sciences, Rush Medical College, Chicago, IL, United States.
⁹ Division of Neurology, Department of Pediatrics, University of British Columbia, BC Children's Hospital, Vancouver, BC, Canada.
¹⁰ Leukodystrophy Center, University of Leipzig Medical Center, Leipzig, Germany.
¹¹ Genomic Medicine Center, Children's Mercy Hospital, Kansas City, MO, United States.
¹² University of Missouri Kansas City School of Medicine, Kansas City, MO, United States.
¹³ Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO, United States.
¹⁴ Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Center, Montreal, QC, Canada.

Abstract

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.

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

Grants and funding

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.