LAUSR

The advent of new, revolutionary biomedical technologies might have far-reaching, transformative consequences for clinical practice and also inevitably will generate debates and controversies, including positions which, at first sight, might sound provocative and futuristic. We are witnessing one such revolution with the advent of novel genetic technologies, collectively termed “next-generation sequencing” (NGS), which are rapidly changing the clinical practice of neurology and challenging the role of clinical expertise. In general, there have been 2 major yields of NGS for genetic medicine: novel, disease-causing genes are being discovered at an unprecedented pace; and phenotypes associated with mutations in a given gene are expanding to much broader spectra of overlapping conditions (sometimes 2 or more discrete syndromes). A very high degree of genetic and clinical heterogeneity is emerging in every chapter of neurogenetics, most spectacularly in the neurodevelopmental disorders, intellectual disabilities, inherited ataxias, and spastic paraplegias but also in monogenic parkinsonisms, dystonias, choreas, paroxysmal dyskinesias, and neurodegenerations with brain metal accumulations. The same clinical phenotype can be caused by mutations in one of a large number of candidate genes (genetic heterogeneity); on the other hand, mutations in the same gene can result in very different phenotypes (clinical heterogeneity). It is more and more difficult for the neurologist to stay abreast with the expanding numbers of diseasecausing genes and their expanding and overlapping phenotypes. Furthermore, the results of NGS studies are blurring the distinctions between “typical” and “atypical” clinical presentations. Thus, what is left for the clinical expertise? Confronted with these complexities, even the most skilled neurologist will not be able to make accurate etiological diagnoses without the aid of rapid, accurate, and comprehensive genetic testing, such as exome or whole-genome sequencing. “Clinical exome sequencing” (CES) is rapidly becoming a state-of-the-art genetic test and is crucially useful for quickly reaching a diagnosis in patients with unspecific, atypical, or otherwise unexplained presentations in which mutations in one of several candidate genes is the suspected etiology. Examples of this abound in both pediatric and adult neurology, including the movement disorders. In these scenarios, CES is superior to the conventional diagnostic work-up: it increases diagnostic rates; shortens the time to diagnosis; avoids several other, often expensive and/or invasive investigations (the “diagnostic odysseys”); and improves patient outcomes. There are important benefits here for the patients, their relatives, the clinicians, and the health system as a whole. Reaching a molecular diagnosis sooner will be much more important when novel therapies will become available based on the molecular fingerprint of the disease in a given patient. Precision medicine is already a reality in oncology, in which the choice of therapeutic strategies relies more and more often on specific tumor molecular signatures, including mutations in causative or modifier genes. For most of the monogenic neurodegenerative conditions, a molecular (etiological) diagnosis does not currently lead to rational therapy. This scenario will hopefully change in the future. However, it is important to remember that reaching an etiological diagnosis has other important advantages for the patient, the family, and the clinicians: reaching the diagnosis often ends (or prevents) diagnostic odysseys, relieves anxiety about the origin of the disease, and allows counselling of relatives, family planning, and implementation of preventive screening. Although further studies are warranted, CES ultimately also may be cheaper than traditional diagnostic procedures, considering that costs of the several other tests can be avoided. One additional advantage is the possibility of simultaneously diagnosing two genetic disorders in the same patient (this might underlie atypical presentations and happens more often than expected). The advantages are so clear that CES is already being evaluated as a first-line diagnostic tool rather than a second or last