Neurology Individualized Medicine: When to Use Next-Generation Sequencing Panels  Christopher J. Klein, MD, Tatiana M. Foroud, PhD  Mayo Clinic Proceedings  Volume 92, Issue 2, Pages 292-305 (February 2017) DOI: 10.1016/j.mayocp.2016.09.008 Copyright © 2016 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 1 The sequencing revolution by next-generation sequencing was afforded by the technological innovation of bridge polymerase chain reaction (PCR) amplification for cluster DNA generation, and massive parallel-sequencing data are aligned back to a reference genome. In whole-genome sequencing, no capture step is required and all intergenic and intragenic regions are sheared and sequenced, whereas whole-exome sequencing evaluates only the expressed regions with use of exome capture kits. Targeted-panel next-generation sequencing utilizes custom-designed baits to capture targeted genes with input from the clinician and laboratory geneticist for a high-performing, disease-focused evaluation. Mayo Clinic Proceedings 2017 92, 292-305DOI: (10.1016/j.mayocp.2016.09.008) Copyright © 2016 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 2 Among Mendelian neurologic disorders, a genetic cause is common. The extent of genetic diversity and number of Mendelian causal genes vary depending on the disease phenotype. The clinical overlap and number of genes are illustrated by overlapping of each circle and the sizes of the circles. The extent of genetic diversity in the specific clinical scenario specifies which genetic test platform will be the best choice. Comprehensive whole-exome or genome sequencing should be considered for patients without a focused genetic differential diagnosis. Mayo Clinic Proceedings 2017 92, 292-305DOI: (10.1016/j.mayocp.2016.09.008) Copyright © 2016 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 3 The decision of which genetic sequencing platform to utilize depends on the genetic diversity of a specific neurologic disorder. Next-generation sequencing (NGS) by whole-exome sequencing is best for “diagnostic odyssey” cases in which neurologic localization is not well established or the genetic differential diagnosis is not limited to any specific disease category. Among those with a defined genetic differential diagnosis, targeted-panel NGS has the best test performance metrics. Certain neurologic phenotypes have very specific characteristics, and single-gene testing remains very effective. Mayo Clinic Proceedings 2017 92, 292-305DOI: (10.1016/j.mayocp.2016.09.008) Copyright © 2016 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 4 Patients who have polyneuropathy with a suspected genetic cause benefit from an algorithmic approach that combines detailed clinical and electrophysiologic features with best genetic testing platforms. Targeted next-generation sequencing provides the best value in making a genetic diagnosis when PMP22 duplication testing results are either negative or not needed on the basis of nerve conduction studies. MRI = magnetic resonance imaging. Mayo Clinic Proceedings 2017 92, 292-305DOI: (10.1016/j.mayocp.2016.09.008) Copyright © 2016 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 5 Epilepsy has a large genetic differential diagnosis. Targeted next-generation sequencing can be helpful for those with a specific epilepsy syndrome. Chromosomal microarray or whole-exome trio evaluations may be considered as the initial testing step, depending on whether a more global cognitive or developmental process is involved. EEG = electroencephalography; EncephChronic = chronic encephalopathy, seizures; FocalSz = focal seizures; InfSpasm = infantile spasms; MRI = magnetic resonance imaging; NeonSz = neonatal seizures; NeuronMigration = neuronal migration; PME = progressive myoclonic epilepsy. Mayo Clinic Proceedings 2017 92, 292-305DOI: (10.1016/j.mayocp.2016.09.008) Copyright © 2016 Mayo Foundation for Medical Education and Research Terms and Conditions