Whole Exome Sequencing in Neurogenetic Diagnostic Odysseys: An Argentinian Experience

ABSTRACT Clinical variability is a hallmark of neurogenetic disorders. They involve widespread neurological entities such as neuropathies, ataxias, myopathies, mitochondrial encephalopathies, leukodystrophies, epilepsy and intellectual disabilities. Despite the use of considerable time and resources, the diagnostic yield in this field has been disappointingly low. This etiologic search has been called a “diagnostic odyssey” for many families. Whole exome sequencing (WES) has proved to be useful across a variety of genetic disorders, simplifying the odyssey of many patients and their families and leading to subsequent changes in clinical management in a proportion of them. Although a diagnostic yield of about 30% in neurogenetic disorders can be extrapolated from the results of large series that have included other medical conditions as well, there are not specific reports assessing its utility in a setting such as ours: a neurogeneticist led academic group serving in a low-income country. Herein, we report on a series of our first 40 consecutive cases that were selected for WES in a research-based neurogenetics laboratory. We demonstrated the clinical utility of WES in our patient cohort, obtaining a diagnostic yield of 40% (95% CI, 24.8%-55.2%), describing cases in which clinical management was altered, and suggesting the potential cost-effectiveness of WES as a single test by examining the number and types of tests that were performed prior to WES which added up to a median cost of $3537.6 ($2892 to $5084) for the diagnostic odysseys experienced by our cohort.