Utility of a Strategic Next Generation Sequencing Approach to Genomic Diagnosis of Patients with Neurodevelopmental Disorders. S. Soden1,2,4, C. Saunders1,2,3,4, E. Farrow1,2,4, N. Miller1,2, L. Smith1,2,4, D. Dinwiddie1,2,3,4,5,6, A. Atherton1,2,4, J. LePichon1,2,4, B. Heese1,2,4, A. Abdelmoity1,2,4, N. Safina1,2,4, A. Modrcin1,2,4, L. Willig1,2,4, S. Kingsmore1,2,3,4 1) Center for Pediatric Genomic Medicine, Childrens Mercy Hospital, Kansas City, Missouri 64108, USA; 2) Department of Pediatrics, Childrens Mercy Hospital, Kansas City, Missouri 64108, USA; 3) Department of Pathology, Childrens Mercy Hospital, Kansas City, Missouri 64108, USA; 4) School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108, USA; 5) Deparment of Pediatrics, University of New Mexico Health Science Center, Albuquerque, New Mexico 87131, USA; 6) Clinical Translational Science Center, University of New Mexico, Albuquerque, New Mexico 87131, USA.

   Background: Nearly 50% of patients with neurodevelopmental disorders do not receive an etiologic diagnosis, despite often lengthy and costly evaluations. Next-generation sequencing (NGS) has the potential to identify a molecular diagnosis in such patients, resulting in improved patient care. Objectives: We present a novel approach to whole genome (WGS), whole exome (WES), and customized NGS panel testing of 107 patients with neurodevelopmental disorders at the Childrens Mercy Hospital Center for Pediatric Genome Medicine (CPGM). Methods: Under a research protocol, patients with neurodevelopmental disabilities were nominated for NGS by treating neurologists, geneticists, rehabilitation specialists, and neurodevelopmental pediatricians. Nominations were reviewed to designate participants for 1 of 3 tests: WGS, WES, or CPGM-developed customized panel. Test selection was based on a structured analysis of clinical features, prior testing, family history, and availability of parents for enrollment. A trio of novel software applications, developed in-house, was used for analysis: Sign and Symptom Assisted Genome Analysis (SSAGA), Rapid Understanding of Nucleotide variant Effect Software (RUNES) and Variant Integration and Knowledge in Genomes (VIKING). These tools tailor variant results by customizing the list of genes analyzed for each patient based on phenotype. Diagnostic genotypes were confirmed with Sanger sequencing and reported to referring physicians. Results: 107 patients with neurodevelopmental disorders, primarily intellectual disability, epilepsy, weakness and regression, were enrolled. Molecular diagnoses were made in 40 of 107 (37%) subjects enrolled: 3 of 4 tested with WGS, 27 of 56 tested with WES, and 10 of 47 tested with the customized panel. Candidate genes were identified in 9 additional subjects by WES, for which functional testing has been initiated. Among patients who received a diagnosis, average age of symptom onset was 12.9 (range 0-90) months, age at enrollment was 84.8 (2-252) months, and age at genomic diagnosis was 99.5 (10-262) months. Referring physicians reported that diagnosis changed management in 10 cases, namely initiation of new treatments, discontinuation of unnecessary medications, and avoidance of invasive procedures. Conclusion: A strategic NGS approach to genomic diagnosis of patients with neurodevelopmental disabilities increases diagnostic yield, is comparatively rapid, and can impact patient care.

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