Solving inherited white matter disorder etiologies in the neurology clinic: Challenges and lessons learned using next-generation sequencing
IntroductionRare 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...
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| Format: | Article |
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Frontiers Media S.A.
2023-04-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fneur.2023.1148377/full |
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| author | Stefanie Perrier Stefanie Perrier Kether Guerrero Kether Guerrero Luan T. Tran Luan T. Tran Mackenzie A. Michell-Robinson Mackenzie A. Michell-Robinson Geneviève Legault Geneviève Legault Geneviève Legault Bernard Brais Bernard Brais Bernard Brais Michel Sylvain James Dorman James Dorman Michelle Demos Wolfgang Köhler Tomi Pastinen Tomi Pastinen Isabelle Thiffault Isabelle Thiffault Isabelle Thiffault Geneviève Bernard Geneviève Bernard Geneviève Bernard Geneviève Bernard Geneviève Bernard |
| author_facet | Stefanie Perrier Stefanie Perrier Kether Guerrero Kether Guerrero Luan T. Tran Luan T. Tran Mackenzie A. Michell-Robinson Mackenzie A. Michell-Robinson Geneviève Legault Geneviève Legault Geneviève Legault Bernard Brais Bernard Brais Bernard Brais Michel Sylvain James Dorman James Dorman Michelle Demos Wolfgang Köhler Tomi Pastinen Tomi Pastinen Isabelle Thiffault Isabelle Thiffault Isabelle Thiffault Geneviève Bernard Geneviève Bernard Geneviève Bernard Geneviève Bernard Geneviève Bernard |
| author_sort | Stefanie Perrier |
| collection | DOAJ |
| description | IntroductionRare 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.MethodsEach 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.ResultsFollowing 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.DiscussionThis 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. |
| first_indexed | 2024-04-09T19:47:05Z |
| format | Article |
| id | doaj.art-f1fdff3b504e41b18a02f8a168cfe29e |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-04-09T19:47:05Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-f1fdff3b504e41b18a02f8a168cfe29e2023-04-03T15:43:30ZengFrontiers Media S.A.Frontiers in Neurology1664-22952023-04-011410.3389/fneur.2023.11483771148377Solving inherited white matter disorder etiologies in the neurology clinic: Challenges and lessons learned using next-generation sequencingStefanie Perrier0Stefanie Perrier1Kether Guerrero2Kether Guerrero3Luan T. Tran4Luan T. Tran5Mackenzie A. Michell-Robinson6Mackenzie A. Michell-Robinson7Geneviève Legault8Geneviève Legault9Geneviève Legault10Bernard Brais11Bernard Brais12Bernard Brais13Michel Sylvain14James Dorman15James Dorman16Michelle Demos17Wolfgang Köhler18Tomi Pastinen19Tomi Pastinen20Isabelle Thiffault21Isabelle Thiffault22Isabelle Thiffault23Geneviève Bernard24Geneviève Bernard25Geneviève Bernard26Geneviève Bernard27Geneviève Bernard28Department of Neurology and Neurosurgery, McGill University, Montreal, QC, CanadaChild Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, CanadaDepartment of Neurology and Neurosurgery, McGill University, Montreal, QC, CanadaChild Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, CanadaDepartment of Neurology and Neurosurgery, McGill University, Montreal, QC, CanadaChild Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, CanadaDepartment of Neurology and Neurosurgery, McGill University, Montreal, QC, CanadaChild Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, CanadaDepartment of Neurology and Neurosurgery, McGill University, Montreal, QC, CanadaChild Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, CanadaDepartment of Pediatrics, McGill University, Montreal, QC, CanadaDepartment of Neurology and Neurosurgery, McGill University, Montreal, QC, CanadaMontreal Neurological Institute, McGill University, Montreal, QC, CanadaDepartment of Human Genetics, McGill University, Montreal, QC, CanadaDivision of Pediatric Neurology, Centre Mère-Enfant Soleil du CHU de Québec - Université Laval, Québec City, QC, CanadaJohn H. Stroger Jr. Hospital of Cook County, Chicago, IL, United StatesDepartment of Neurological Sciences, Rush Medical College, Chicago, IL, United StatesDivision of Neurology, Department of Pediatrics, University of British Columbia, BC Children's Hospital, Vancouver, BC, Canada0Leukodystrophy Center, University of Leipzig Medical Center, Leipzig, Germany1Genomic Medicine Center, Children's Mercy Hospital, Kansas City, MO, United States2University of Missouri Kansas City School of Medicine, Kansas City, MO, United States1Genomic Medicine Center, Children's Mercy Hospital, Kansas City, MO, United States2University of Missouri Kansas City School of Medicine, Kansas City, MO, United States3Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO, United StatesDepartment of Neurology and Neurosurgery, McGill University, Montreal, QC, CanadaChild Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, CanadaDepartment of Pediatrics, McGill University, Montreal, QC, CanadaDepartment of Human Genetics, McGill University, Montreal, QC, Canada4Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Center, Montreal, QC, CanadaIntroductionRare 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.MethodsEach 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.ResultsFollowing 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.DiscussionThis 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.https://www.frontiersin.org/articles/10.3389/fneur.2023.1148377/fullleukodystrophyhypomyelinationnext generation sequencing (NGS)genetic diagnosismedical geneticspediatric neurology |
| spellingShingle | Stefanie Perrier Stefanie Perrier Kether Guerrero Kether Guerrero Luan T. Tran Luan T. Tran Mackenzie A. Michell-Robinson Mackenzie A. Michell-Robinson Geneviève Legault Geneviève Legault Geneviève Legault Bernard Brais Bernard Brais Bernard Brais Michel Sylvain James Dorman James Dorman Michelle Demos Wolfgang Köhler Tomi Pastinen Tomi Pastinen Isabelle Thiffault Isabelle Thiffault Isabelle Thiffault Geneviève Bernard Geneviève Bernard Geneviève Bernard Geneviève Bernard Geneviève Bernard Solving inherited white matter disorder etiologies in the neurology clinic: Challenges and lessons learned using next-generation sequencing Frontiers in Neurology leukodystrophy hypomyelination next generation sequencing (NGS) genetic diagnosis medical genetics pediatric neurology |
| title | Solving inherited white matter disorder etiologies in the neurology clinic: Challenges and lessons learned using next-generation sequencing |
| title_full | Solving inherited white matter disorder etiologies in the neurology clinic: Challenges and lessons learned using next-generation sequencing |
| title_fullStr | Solving inherited white matter disorder etiologies in the neurology clinic: Challenges and lessons learned using next-generation sequencing |
| title_full_unstemmed | Solving inherited white matter disorder etiologies in the neurology clinic: Challenges and lessons learned using next-generation sequencing |
| title_short | Solving inherited white matter disorder etiologies in the neurology clinic: Challenges and lessons learned using next-generation sequencing |
| title_sort | solving inherited white matter disorder etiologies in the neurology clinic challenges and lessons learned using next generation sequencing |
| topic | leukodystrophy hypomyelination next generation sequencing (NGS) genetic diagnosis medical genetics pediatric neurology |
| url | https://www.frontiersin.org/articles/10.3389/fneur.2023.1148377/full |
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