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.

BackgroundThe aim of this study was to assess the diagnostic accuracy (sensitivity and specificity) of clinical, imaging and motor evoked potentials (MEP) for predicting the short-term prognosis of multiple sclerosis (MS).MethodsWe obtained clinical data, MRI and MEP from a prospective cohort of 51 patients and 20 matched controls followed for two years. Clinical end-points recorded were: 1) expanded disability status scale (EDSS), 2) disability progression, and 3) new relapses. We constructed computational classifiers (Bayesian, random decision-trees, simple logistic-linear regression-and neural networks) and calculated their accuracy by means of a 10-fold cross-validation method. We also validated our findings with a second cohort of 96 MS patients from a second center.ResultsWe found that disability at baseline, grey matter volume and MEP were the variables that better correlated with clinical end-points, although their diagnostic accuracy was low. However, classifiers combining the most informative variables, namely baseline disability (EDSS), MRI lesion load and central motor conduction time (CMCT), were much more accurate in predicting future disability. Using the most informative variables (especially EDSS and CMCT) we developed a neural network (NNet) that attained a good performance for predicting the EDSS change. The predictive ability of the neural network was validated in an independent cohort obtaining similar accuracy (80%) for predicting the change in the EDSS two years later.ConclusionsThe usefulness of clinical variables for predicting the course of MS on an individual basis is limited, despite being associated with the disease course. By training a NNet with the most informative variables we achieved a good accuracy for predicting short-term disability.

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IntroductionClinical genomics promise to be especially suitable for the study of etiologically heterogeneous conditions such as Autism Spectrum Disorder (ASD). Here we present three siblings with ASD where we evaluated the usefulness of Whole Genome Sequencing (WGS) for the diagnostic approach to ASD.MethodsWe identified a family segregating ASD in three siblings with an unidentified cause. We performed WGS in the three probands and used a state-of-the-art comprehensive bioinformatic analysis pipeline and prioritized the identified variants located in genes likely to be related to ASD. We validated the finding by Sanger sequencing in the probands and their parents.ResultsThree male siblings presented a syndrome characterized by severe intellectual disability, absence of language, autism spectrum symptoms and epilepsy with negative family history for mental retardation, language disorders, ASD or other psychiatric disorders. We found germline mosaicism for a heterozygous deletion of a cytosine in the exon 21 of the SHANK3 gene, resulting in a missense sequence of 5 codons followed by a premature stop codon (NM_033517:c.3259_3259delC, p.Ser1088Profs*6).ConclusionsWe reported an infrequent form of familial ASD where WGS proved useful in the clinic. We identified a mutation in SHANK3 that underscores its relevance in Autism Spectrum Disorder.