BackgroundDiagnostic trajectories for neurogenetic disorders frequently require the use of considerable time and resources, exposing patients and families to so-called “diagnostic odysseys”. Previous studies have provided strong evidence for increased diagnostic and clinical utility of whole-exome sequencing in medical genetics. However, specific reports assessing its utility in a setting such as ours- a neurogeneticist led academic group serving in a low-income country—are rare.ObjectivesTo assess the diagnostic yield of WES in patients suspected of having a neurogenetic condition and explore the cost-effectiveness of its implementation in a research group located in an Argentinean public hospital.MethodsThis is a prospective study of the clinical utility of WES in a series of 40 consecutive patients selected from a Neurogenetic Clinic of a tertiary Hospital in Argentina. We evaluated patients retrospectively for previous diagnostic trajectories. Diagnostic yield, clinical impact on management and economic diagnostic burden were evaluated.ResultsWe demonstrated the clinical utility of Whole Exome Sequencing in our patient cohort, obtaining a diagnostic yield of 40% (95% CI, 24.8%-55.2%) among a diverse group of neurological disorders. The average age at the time of WES was 23 (range 3–70). The mean time elapsed from symptom onset to WES was 11 years (range 3–42). The mean cost of the diagnostic workup prior to WES was USD 1646 (USD 1439 to 1853), which is 60% higher than WES cost in our center.ConclusionsWES for neurogenetics proved to be an effective, cost- and time-saving approach for the molecular diagnosis of this heterogeneous and complex group of patients.

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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 &

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Schizophrenia (SZ) is a disorder with a high heritability and a complex architecture. Several dozen genetic variants have been identified as risk factors through genome-wide association studies including large population-based samples. However, the bulk of the risk cannot be accounted for by the genes associated to date. Rare mutations have been historically seen as relevant only for some infrequent, Mendelian forms of psychosis. Recent findings, however, show that the subset of patients that present a mutation with major effect is larger than expected. We discuss some of the molecular findings of these studies. SZ is clinically and genetically heterogeneous. To identify the genetic variation underlying the disorder, research should be focused on features that are more likely a product of genetic heterogeneity. Based on the phenotypical correlations with rare variants, cognition emerges as a relevant domain to study. Cognitive disturbances could be useful in selecting cases that have a higher probability of carrying deleterious mutations, as well as on the correct ascertainment of sporadic cases for the identification of de novo variants.

INTRODUCCIÓN El sabor dulce juega un rol muy importante en los seres humanos, ya que la mayoría de las personas responden positivamente a la sensación de dulzor, y existe una propensión al consumo de alimentos dulces que se remonta a la vida temprana (1). Los edulcorantes utilizados en la industria alimentaria se dividen en 2 grandes grupos: calóricos y no calóricos. Entre los edulcorantes no calóricos de mayor consumo se encuentran la sacarina de sodio cuyo poder edulcorante es 200 a 700 superior al azúcar, la sucralosa que es 600 veces más dulce que el azúcar, la estevia cuyo poder es 300 veces mayor que el azúcar y Aspartamo 200 veces más dulce que el azúcar (2,3). Actualmente, los edulcorantes no calóricos han ganado una mayor presencia en la alimentación, no tan sólo de personas diabéticas o con dietas hipocalóricas, si no que de personas sin patologías que han decidido disminuir el consumo del azúcar (sacarosa). Los edulcorantes no calóricos son utilizados como reemplazo total o parcial de la sacarosa; además, poseen un mayor poder endulzante que ésta (2). Se discute que los edulcorantes no poseen un poder saciador como el azúcar, inclusive podrían causar la sensación

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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.