| Affiliation: | 1. Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA;2. Lurie Children's Hospital, Chicago, Illinois, USA;3. Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA;4. Department of Molecular & Human Genetics, Baylor College of Medicine, and Baylor Genetics Laboratories, Houston, Texas, USA;5. EGL Genetics, Tucker, Georgia, USA;6. GeneDx, Gaithersburg, Maryland, USA;7. Invitae, San Francisco, California, USA;8. Ambry Genetics, Aliso Viejo, California, USA;9. Nemours/Alfred I duPont Hospital for Children, Wilmington, Delaware, USA;10. Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA;11. Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California, USA;12. Department of Human Genetics, University of California Los Angeles, Los Angeles, California, USA;13. Natera Inc., San Carlos, California, USA;14. CooperGenomics, Livingston, New Jersey, USA;15. Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, University of Missouri‐Kansas City School of Medicine, Kansas City, Missouri, USA;16. Biogen, Cambridge, Massachusetts, USA;17. Murdoch Children' Research Institute, The Royal Children's Hospital, Parkville, Australia;18. Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia;19. https://orcid.org/0000-0002-6290-6751;20. Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA;21. Adeline Vanderver, MD, 3615 Civic Center Blvd., Philadelphia, PA 19104. |
| Abstract: | Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. We assessed the relative frequency of all 30 leukodystrophies (associated with 55 genes) in more than 49,000 exomes. We identified a relatively high frequency of disorders previously thought of as very rare, including Aicardi Goutières Syndrome, TUBB4A‐related leukodystrophy, Peroxisomal biogenesis disorders, POLR3‐related Leukodystrophy, Vanishing White Matter, and Pelizaeus‐Merzbacher Disease. Despite the relative frequency of these conditions, carrier‐screening laboratories regularly test only 20 of the 55 leukodystrophy‐related genes, and do not test at all, or test only one or a few, genes for some of the higher frequency disorders. Relative frequency of leukodystrophies previously considered very rare suggests these disorders may benefit from expanded carrier screening. |
