Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent-offspring trio exome sequencing in 231 individuals with NDDs. Phenotypes were compiled using human phenotype ontology terms. The overall diagnostic yield was 49.8% (n = 115/231) with de novo variants contributing to more than 80% (n = 93/115) of all solved cases. De novo variants affected 72 different-mostly constrained-genes. In addition, we identified putative pathogenic variants in 16 genes not linked to NDDs to date. Reanalysis performed in 80 initially unsolved cases revealed a definitive diagnosis in two additional cases. Our study consolidates the contribution and genetic heterogeneity of de novo variants in NDDs highlighting trio exome sequencing as effective diagnostic tool for NDDs. Besides, we illustrate the potential of a trio-approach for candidate gene discovery and the power of systematic reanalysis of unsolved cases.

Department of General Pediatrics Neonatology and Pediatric Cardiology Heinrich Heine University Düsseldorf Germany

Department of Nephrology Klinikum rechts der Isar Technical University of Munich Munich Germany

Department of Neurology Charles University 1st Faculty of Medicine and General University Hospital Prague Prague Czech Republic

Department of Neurology P J Safarik University Kosice Slovakia

Department of Neurology University Hospital L Pasteur Kosice Slovakia

Department of Neurology Zvolen Hospital Zvolen Slovakia

Department of Paediatric Neurology and Developmental Medicine Hauner Children's Hospital University of Munich Munich Germany

Department of Pediatrics Technische Universität München Munich Germany

Division of Child Neurology and Inherited Metabolic Diseases Centre for Paediatrics and Adolescent Medicine University Hospital Heidelberg Heidelberg Germany

Division of Pediatric Neurology University Children's Hospital Zurich Zurich Switzerland

Divison of Neuropediatrics Clinic for Children and Adolescents Dritter Orden Munich Germany

Institute of Human Genetics Helmholtz Zentrum München Neuherberg Germany

Institute of Human Genetics Klinikum rechts der Isar School of Medicine Technical University of Munich Munich Germany

Institute of Human Genetics University Hospital Ludwig Maximilians University of Munich Munich Germany

Institute of Human Genetics University Medical Center Hamburg Eppendorf Hamburg Germany

Institute of Neurogenomics Helmholtz Zentrum München Neuherberg Germany

Medical Department 1 Cardiology Klinikum rechts der Isar Technical University of Munich Munich Germany

Munich Cluster for Systems Neurology Munich Germany

Neurogenetics Technische Universität München Munich Germany

Paracelsus Elena Klinik Kassel Germany

Praxis für Humangenetik Ulm Germany

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