The utility of whole exome sequencing in the investigation of the genetic etiologies of leukodystrophies and genetic leukoencephalopathies.


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Leukodystrophies and genetic leukoencephalopathies are diseases of the white matter in the central nervous system making up over 100 distinct genetic disorders, and their paradoxical heterogenic but overlapping clinical manifestations make it difficult to identify their genetic etiologies. This creates a diagnostic challenge for clinicians as approximately half of all patients with white matter abnormalities remain diagnostically unresolved after extensive neuroimaging, biochemical investigation, and genetic single gene interrogation. This failure burdens the patients and their families with a lengthy, expensive, and invasive diagnostic odyssey with no resolution. In contrast, next generation sequencing offers the potential to achieve a diagnosis in a shorter amount of time and at a lower cost with a single DNA-based test through the targeted capture of exomes and whole exome sequencing. At the onset of this study, whole exome sequencing had never before been applied to the leukodystrophies. Whole exome sequencing was performed on a cohort of patients with unsolved white matter abnormalities with a suspected leukodystrophy or genetic leukoencephalopathy diagnosis. Out of 10 families with unresolved leukodystrophies, novel or rare pathogenic variants in 4 known leukodystrophy or genetic leukoencephalopathy genes, STXBP1, ALS2, EARS2, and PLP1, were identified in 4 unrelated patients each with a different disease manifestation. Additionally, with collaboraters, a novel de novo pathogenic variant in TUBB4A was identified in patients with a known leukodystrophy which was not previously associated with any leukodystrophy or genetic leukoencephalopathy. Variant pathogenicity characterization was validated with bioinformatics interrogation and in-vitro functional assays following guidelines set forth by different clinical genetic associations. The remaining cases in the cohort were unable to be resolved due to low sequence coverage, limited power from small family analysis, or through genetic factors that cannot be stratified with whole exome sequencing. These findings suggest that whole exome sequencing can identify the underlying genetic etiology of unsolved leukodystrophies or genetic leukoencephalopathies in some cases, and with proper guidelines and standards, it merits clinical diagnostic use due to the broad clinical and genetic spectrum of these disorders.



Sequencing. Leukodystrophy.