During the last decade, incredible improvements in the speed, accuracy and cost-effectiveness of whole-genome sequencing have accelerated our understanding of genetic disorders. An international Leukodystrophy Study Group, including researchers with Baylor Scott & White Research Institute (BSWRI), has used these next-generation sequencing methods to reveal the genetic abnormalities in a cohort of 71 persistently undiagnosed individuals with suspected leukodystrophy. Leukodystrophies are rare genetic disorders that disrupt the myelin sheath, which forms the white matter in the brain.

The challenge of leukodystrophy. Patients with white matter abnormalities present with a wide range of symptoms that confound differential diagnosis. Of the potential white matter disorders, leukodystrophies are a heterogeneous class of heritable demyelinating or hypomyelinating diseases with onset in either childhood or adulthood. The most common leukodystrophy is X-linked adrenoleukodystrophy, which is caused by a defect in the gene encoding the ABCD1fatty acid transporter. Among the more than 40 identified leukodystrophies, most involve disruption of genes encoding proteins regulating the metabolism and transport of fatty acids, which form the myelin sheath. Despite the likely existence of a pathologic gene variant underlying all the leukodystrophies, about half of patients with suspected leukodystrophy still do not get a clear diagnosis.

Identification of novel pathologic gene variants. In 2016, the Leukodystrophy Study Group published their initial whole-genome sequencing effort, which identified likely pathogenic gene variants for 42% of the 71-person cohort with suspected leukodystrophy (Annals of Neurology). In the current publication, released in March 2020 in the Annals of Clinical and Translational Neurology, they used advanced methods to establish a diagnosis in another 14 patients, for a total of 62% of patients with resolved diagnoses in the cohort.

For the new variants, 9 were identified due to improvements in curation of disease-causing variants or due to the identification of new disease-associated genes since their prior analysis. The remaining identified genetic aberrations were copy number variants, variants in deep intronic regions, or variants in technically challenging areas of the genome, all of which were not possible to identify in the prior study. All potentially causal gene variants were evaluated using American College of Medical Genetics guidelines. The new findings included variants in 5 genes previously associated with white matter disease. Only 20% of the genes identified in the combined genome sequencing studies were associated with established leukodystrophy genes, highlighting the importance of advanced genomics in discovering the underlying basis of these rare brain disorders.

The authors mention that their data support the diagnostic use of broad-based next-generation sequencing if biochemical, enzymatic, and MRI testing results do not fit the pattern of an established leukodystrophy. Furthermore, their data support the use of whole-genome rather than whole-exome sequencing because important variants may exist in intronic sites.

Raphael Schiffmann, MD was a member of the Leukodystrophy Study Group and an author on both publications. Dr. Schiffmann’s research specializes in the diagnosis and treatment of neurometabolic diseases and has provided insights into leukodystrophies, Gaucher disease, mucolipidosis, and Fabry disease, among other disorders.