Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with identical missense mutations. One recurrent site substitution (p.A636T) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.

Center for Applied Genomics The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA

Centre for Human Genetics KU Leuven and Leuven Autism Research Leuven Belgium

Department of Biology and Medical Genetics Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden

Department of Clinical Genetics Leiden University Medical Center Leiden the Netherlands

Department of Genome Sciences University of Washington Seattle Washington USA

Department of Medical Genetics University of Antwerp Antwerp Belgium

Department of Molecular Medicine and Surgery Center for Molecular Medicine Karolinska Institutet Stockholm Sweden

Department of Pediatrics Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA

Department of Pharmacology University of Washington Seattle Washington USA

Department of Psychiatry and Behavioral Sciences University of Washington Seattle Washington USA

Department of Psychiatry The University of Iowa Iowa City Iowa USA

Division of Genetics The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA

Howard Hughes Medical Institute Seattle Washington USA

Laboratory of Medical Genetics IRCCS Associazione Oasi Maria Santissima Troina Italy

Robinson Research Institute and the University of Adelaide at the Women's and Children's Hospital North Adelaide South Australia Australia

SA Pathology Adelaide South Australia Australia

School of Medicine University of Adelaide Adelaide South Australia Australia

School of Paediatrics and Reproductive Health University of Adelaide Adelaide South Australia Australia

South Australian Clinical Genetics Service SA Pathology Adelaide South Australia Australia

South Australian Health and Medical Research Institute Adelaide South Australia Australia

The State Key Laboratory of Medical Genetics School of Life Sciences Central South University Changsha Hunan China

Unit of Neurology IRCCS Associazione Oasi Maria Santissima Troina Italy

Unit of Pediatrics and Medical Genetics IRCCS Associazione Oasi Maria Santissima Troina Italy

University of California San Diego Autism Center of Excellence La Jolla California USA

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Delineation of functionally essential protein regions for 242 neurodevelopmental genes

DNA Methylation, Deamination, and Translesion Synthesis Combine to Generate Footprint Mutations in Cancer Driver Genes in B-Cell Derived Lymphomas and Other Cancers

Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders