ES demonstrates a 20-50 percent diagnostic yield for patients with a suspected monogenic neurologic disease. Despite the proven efficacy in achieving a diagnosis for such patients, multiple barriers for obtaining exome sequencing remain.

A total of 297 patients were identified from the UCLA Clinical Neurogenomics Research Center Biobank and ES was performed, including bioinformatic assessment of copy number variation and repeat expansions. Information regarding demographics, clinical indication for ES, and reason for not pursuing ES clinically were recorded. To assess diagnostic efficacy, variants were interpreted by a multidisciplinary team of clinicians, bioinformaticians, and genetic counselors in accordance with the ACMG variant classification guidelines. We next examined the specific barriers to testing for these patients, including how frequently insurance-related barriers such as coverage denials and inadequate coverage of cost were obstacles to pursuing exome sequencing.

The cohort primarily consisted of patients with sporadic conditions (n=126, 42.4%) of adult-onset (n=239, 80.4%). Cerebellar ataxia (n=225, 75.8%) was the most common phenotype. 47 patients (15.8%) had diagnostic ES results, while an additional 24 patients (8.1%) had uncertain results. Incorporation of bioinformatic repeat expansion testing was valuable, identifying a total of eight pathogenic repeat expansions (17.0% of all diagnostic findings). Of the 297 patients, 206 were initially recommended for clinical exome but 88 (42.7%) could not pursue ES due to insurance barriers, of which 14 (15.9%) had diagnostic findings, representing 29.8% of all subjects with diagnostic findings.

These findings underscore the importance clinical ES as a diagnostic tool for neurogenetic disease and highlight key barriers that prevent patients from receiving important clinical information with potential treatment and psychosocial implications for patients and family members.