Whole exome sequencing (WES) represents a significant breakthrough in clinical genetics as a powerful tool for etiological discovery in neurodevelopmental disorders. The high diagnostic yield of WES supports its use in pediatric neurology practices. It may also lead to earlier diagnosis, impacting medical management, prognostication, and family planning. WES therefore serves as a critical tool for the childneurologist. Having said that a number of challenges need to be resolved before whole exome sequencing can be implemented as a standard of care in the clinical setting.
The three challenges that were most consistently reported by technology users were that of incidental findings, variants of unknown significance, and the cost of the technology. Although a small number of challenges, notably communication with patients, education of clinicians, and patients’ turnaround time, were reported differently in articles focusing on cancer, rare diseases or all diseases, and in articles from different countries, most challenges were discussed similarly across diseases and countries (data not shown).
WES is already used in the clinical setting, and may soon be considered the standard of care for specific medical conditions, most notably for the identification of mutations contributing to rare genetic diseases. Clinics in the USA, France and the Netherlands already report promising results from the systematic use of NGS in hundreds of patients. Yet, technology users are calling for certain standards and guidelines to be published before this technology replaces more focused approaches such as gene panels sequencing. In addition, it is clear that a number of infrastructural adjustments will have to be made for clinics to store, process and analyze the amounts of data produced by WES.
The interpretation of this data requires specially trained staff, and patients and families must also be adequately prepared to deal with WES test results. Some intermediary solutions may be found, such as the one suggested by Topper et al.: “In the near term, we suggest that many of these technical and ethical challenges may be alleviated by a targeted analysis approach, in which the full exome sequence is generated in patients, but analysis is initially limited to those genes already known to play a role in the presenting disorder”. At Kids Neuro Clinic and Rehab Center we do refer patients for whole exome sequencing for evaluation of unexplained delayed milestones ,epilepsies, metabolic diseases and many more.