Genetic and genomic testing for neurologic disease in clinical practice

The influence of genetics on neurologic disease is broad and it is becoming more common that clinicians are presented with a patient whose disease is likely of genetic origin. In the search for mutations causing Mendelian disorders, advances in genetic testing methodology have propelled modern neurologic practice beyond single-gene testing into the realm of genomic medicine, where routine evaluations encompass hundreds or thousands of genes, or even the entire exome, representing all protein-coding genes in the genome. The role of various single-gene, multigene, and genomic testing methods, including chromosomal microarray and next-generation sequencing, in the evaluation of neurologic disease is discussed here to provide a framework for their use in a modern neurologic practice. Understanding the inherent issues that arise during the interpretation of sequence variants as pathogenic or benign and the potential discovery of incidental medically relevant findings are important considerations for neurologists utilizing these tests clinically. Strategies for the evaluation of clinically heterogeneous disorders are presented to guide neurologists in the transition from single-gene to genomic considerations and toward the prospect of the widespread routine use of exome sequencing in the continuing goal to achieve more rapid and more precise diagnoses that will improve management and outcome in patients challenged by neurologic disease.