Cross-Sectional Analysis of Exome Sequencing Diagnosis in Patients With Neurologic Phenotypes Facing Barriers to Clinical Testing

Abstract

Background and objectives: Exome sequencing (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. This study set out to assess the efficacy of ES in patients with primary neurologic phenotypes who were appropriate candidates for testing but had been unable to pursue clinical testing.

Methods: 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 American College of Medical Genetics and Genomics 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.

Results: The cohort primarily consisted of patients with sporadic conditions (n = 126, 42.4%) of adult-onset (n = 239, 80.5%). Cerebellar ataxia (n = 225, 75.8%) was the most common presenting neurologic phenotype. Our study found that in this population of mostly adult patients with primary neurologic phenotypes that were unable to pursue exome sequencing clinically, 47 (15.8%) had diagnostic results while an additional 24 patients (8.1%) had uncertain results. Of the 297 patients, 206 were initially recommended for clinical exome but 88 (42.7%) could not pursue ES because of insurance barriers, of whom 14 (15.9%) had diagnostic findings, representing 29.8% of all patients with diagnostic findings. In addition, the incorporation of bioinformatic repeat expansion testing was valuable, identifying a total of 8 pathogenic repeat expansions (17.0% of all diagnostic findings) including 3 of the common spinocerebellar ataxias and 2 patients with Huntington disease.

Discussion: These findings underscore the importance and value of 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.

Figure. Exome Sequencing Results and Most Common Gene-Disease Associations Identified

(A) Exome sequencing results for all 297 patients are depicted. For patients with diagnostic findings (n = 47), the results are broken down into zygosity and shown as percentage of pathogenic results; heterozygous, compound heterozygous, homozygous, repeat expansion, copy number variant, aneuploidy, and mitochondrial DNA. A total of 24 patients had uncertain findings. Eleven patients (3.7%) had secondary findings, 3 had both a P/LP and a secondary finding, 2 had both a VUS and secondary finding. (B) Depicted are the gene-disease associations identified via exome sequencing. Genes are grouped on the basis of their typical phenotypic classification which, because of clinical variability of these disorders, may not reflect the presenting phenotype of all the patients diagnosed in this study (see eTables 1 and 2). Of the 47 patients with diagnostic findings, 15 patients had pathogenic variants identified in genes associated with spastic paraplegia, with SPG7, being the most common seen in 8 patients. The next most common disease was spinocerebellar ataxia, identified in 15 patients. Parkinson disease, basal ganglia calcifications, and Huntington disease were the other diseases identified in more than one patient (n = 3, n = 3, and n = 3, respectively). A total of 9 additional gene-disease associations were identified in only one patient in the cohort.