Clinical application of next-generation sequencing to the practice of neurology

Abstract

Next-generation sequencing technologies allow for rapid and inexpensive large-scale genomic analysis, creating unprecedented opportunities to integrate genomic data into the clinical diagnosis and management of neurological disorders. However, the scale and complexity of these data make them difficult to interpret and require the use of sophisticated bioinformatics applied to extensive datasets, including whole exome and genome sequences. Detailed analysis of genetic data has shown that accurate phenotype information is essential for correct interpretation of genetic variants and might necessitate re-evaluation of the patient in some cases. A multidisciplinary approach that incorporates bioinformatics, clinical evaluation, and human genetics can help to address these challenges. However, despite numerous studies that show the efficacy of next-generation sequencing in establishing molecular diagnoses, pathogenic mutations are generally identified in fewer than half of all patients with genetic neurological disorders, exposing considerable gaps in the understanding of the human genome and providing opportunities to focus research on improving the usefulness of genomics in clinical practice. Looking forward, the emergence of precision health in neurological care will increasingly apply genomic data analysis to pharmacogenetics, preventive medicine, and patient-targeted therapies.

Figure 1:. Proportion of patients molecularly diagnosed with various neurological diseases by whole exome sequencing

The percentage and ratio of patients with a positive genetic diagnosis is indicated for a variety of neurological diseases tested by whole exome sequencing. The total number of patients whose exomes were sequenced is indicated on the X-axis for each neurological disorder and reflected in the relative size of each data point. Studies^,,– from which data were obtained were included on the basis of the disease under investigation and whether exome sequencing was done in the context of a clinical diagnostic test. Studies exclusively using next-generation sequencing panels or partial exomes were not included. *Might include developmental delay. †Includes developmental delay, intellectual disability, and autism spectrum disorder.

Figure 2:. General strategy for incorporating next-generation sequencing into the diagnostic evaluation of a patient with suspected neurogenetic disease

A generic workflow for a diagnostic genetic assessment incorporating next-generation sequencing (blue) and specifically whole exome sequencing is proposed, according to the following sequence: (1) establish phenotype; (2) confirm indication for genetic testing; (3) high-yield testing done on the basis of phenotype or if the most common genetic causes are not detectable by sequencing (eg, nucleotide repeat expansion, deletion, duplication, etc); (4) if advanced genetic testing is necessary, consider the specific disorder or phenotype to determine the most appropriate test; (5) if no diagnosis is achieved with whole exome sequencing, consider regular clinical and bioinformatic re-analysis; after which (6) consider whole genome sequencing for any future analysis, if available. *If considering high-yield single-gene testing of more than 1–3 genes by another sequencing method, note that next-generation sequencing is often most cost-effective. †Genetic counselling is required before and after all genetic testing; other considerations include the potential for secondary findings in genomic testing, testing parents if inheritance is sporadic or recessive, and specialty referral. Modified from Fogel, by permission of Elsevier.