The genetic and phenotypic heterogeneity of neurogenetic diseases forces patients and their families into a "diagnostic odyssey." An increase in the variability of genetic disorders and the corresponding gene-disease associations suggest the need to periodically re-evaluate the significance of variants of undetermined pathogenicity. Here, we report the diagnostic and clinical utility of Targeted Gene Panel Sequencing (TGPS) and Whole Exome Sequencing (WES) in 341 patients with suspected neurogenetic disorders from centers in Buenos Aires and Cincinnati over the last 4 years, focusing on the usefulness of reinterpreting variants previously classified as of uncertain significance. After a mean of ±2years (IC 95:0.73-3.27), approximately 30% of the variants of uncertain significance were reclassified as pathogenic. The use of next generation sequencing methods has facilitated the identification of both germline and mosaic pathogenic variants, expanding the diagnostic yield. These results demonstrate the high clinical impact of periodic reanalysis of undetermined variants in clinical neurology. K E Y W O R D S diagnostic odyssey, mosaicism, targeted gene panel sequencing, variants of unknown significance, whole exome sequencing 1 | INTRODUCTION Neurogenetic diseases encompass a vast group of entities with marked genetic and phenotypic heterogeneity. Nowadays, the process of establishing a diagnosis for this subset of neurological conditions requires extensive clinical, radiological, and genetic evaluations, often becoming a "diagnostic odyssey" for the patient and the family (Carmichael, Tsipis, Windmueller, Mandel, & Estrella, 2015). Next Generation Sequencing (NGS) has become a widely used tool for obtaining genetic diagnosis in clinical medicine (Might &
This study was approved by the Institutional Ethics Committee of the Hospital JM Ramos Mejia of Buenos Aires, Argentina. All patients and parents provided written informed consent for genetic analyses and use of their anonymized data. All experiments and methods were carried out in accordance with the relevant guidelines and regulations of the Institutional Ethics Committee of the Hospital JM Ramos Mejia of Buenos Aires, Argentina. All clinical investigations have been conducted in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.Consent to participate: Informed consent for genetic analyses and use of their anonymized data, was obtained from all individual participants and/or parents included in the study.
Consent to publish: Patients signed informed consent regarding publishing their dataAll rights reserved. No reuse allowed without permission.
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