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      Targeted sequencing identifies 91 neurodevelopmental disorder risk genes with autism and developmental disability biases

      research-article
      1 , 1 , 2 , 1 , 3 , 1 , 4 , 5 , 6 , 7 , 8 , 8 , 9 , 1 , 1 , 1 , 10 , 10 , 10 , 10 , 10 , 11 , 12 , 13 , 13 , 11 , 13 , 11 , 11 , 14 , 6 , 7 , 6 , 7 , 6 , 7 , 15 , 16 , 16 , 16 , 17 , 17 , 17 , 17 , 18 , 19 , 19 , 19 , 19 , 20 , 21 , 22 , 23 , 21 , 24 , 25 , 21 , 25 , 26 , 4 , 5 , 4 , 5 , 3 , 9 , 6 , 7 , 4 , 5 , 8 , 1 , 27
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          Abstract

          Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 patients and >2,867 controls. We report 91 genes with an excess of de novo mutations or private disruptive mutations in 5.7% of patients, including 38 novel NDD genes. Drosophila functional assays of a subset bolster their involvement in NDDs. We identify 25 genes that show a bias for autism versus intellectual disability and highlight a network associated with high-functioning autism (FSIQ>100). Clinical follow-up for NAA15, KMT5B, and ASH1L reveals novel syndromic and non-syndromic forms of disease.

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          Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.

          Noonan syndrome (MIM 163950) is an autosomal dominant disorder characterized by dysmorphic facial features, proportionate short stature and heart disease (most commonly pulmonic stenosis and hypertrophic cardiomyopathy). Webbed neck, chest deformity, cryptorchidism, mental retardation and bleeding diatheses also are frequently associated with this disease. This syndrome is relatively common, with an estimated incidence of 1 in 1,000-2,500 live births. It has been mapped to a 5-cM region (NS1) [corrected] on chromosome 12q24.1, and genetic heterogeneity has also been documented. Here we show that missense mutations in PTPN11 (MIM 176876)-a gene encoding the nonreceptor protein tyrosine phosphatase SHP-2, which contains two Src homology 2 (SH2) domains-cause Noonan syndrome and account for more than 50% of the cases that we examined. All PTPN11 missense mutations cluster in interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of two N-SH2 mutants indicates that in these mutants there may be a significant shift of the equilibrium favoring the active conformation. This implies that they are gain-of-function changes and that the pathogenesis of Noonan syndrome arises from excessive SHP-2 activity.
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            Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study.

            To quantify developmental abnormalities in cerebral and cerebellar volume in autism. The authors studied 60 autistic and 52 normal boys (age, 2 to 16 years) using MRI. Thirty autistic boys were diagnosed and scanned when 5 years or older. The other 30 were scanned when 2 through 4 years of age and then diagnosed with autism at least 2.5 years later, at an age when the diagnosis of autism is more reliable. Neonatal head circumferences from clinical records were available for 14 of 15 autistic 2- to 5-year-olds and, on average, were normal (35.1 +/- 1.3 cm versus clinical norms: 34.6 +/- 1.6 cm), indicative of normal overall brain volume at birth; one measure was above the 95th percentile. By ages 2 to 4 years, 90% of autistic boys had a brain volume larger than normal average, and 37% met criteria for developmental macrencephaly. Autistic 2- to 3-year-olds had more cerebral (18%) and cerebellar (39%) white matter, and more cerebral cortical gray matter (12%) than normal, whereas older autistic children and adolescents did not have such enlarged gray and white matter volumes. In the cerebellum, autistic boys had less gray matter, smaller ratio of gray to white matter, and smaller vermis lobules VI-VII than normal controls. Abnormal regulation of brain growth in autism results in early overgrowth followed by abnormally slowed growth. Hyperplasia was present in cerebral gray matter and cerebral and cerebellar white matter in early life in patients with autism.
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              Database resources of the National Center for Biotechnology.

              D Wheeler (2003)
              In addition to maintaining the GenBank(R) nucleic acid sequence database, the National Center for Biotechnology Information (NCBI) provides data analysis and retrieval resources for the data in GenBank and other biological data made available through NCBI's Web site. NCBI resources include Entrez, PubMed, PubMed Central (PMC), LocusLink, the NCBITaxonomy Browser, BLAST, BLAST Link (BLink), Electronic PCR (e-PCR), Open Reading Frame (ORF) Finder, References Sequence (RefSeq), UniGene, HomoloGene, ProtEST, Database of Single Nucleotide Polymorphisms (dbSNP), Human/Mouse Homology Map, Cancer Chromosome Aberration Project (CCAP), Entrez Genomes and related tools, the Map Viewer, Model Maker (MM), Evidence Viewer (EV), Clusters of Orthologous Groups (COGs) database, Retroviral Genotyping Tools, SAGEmap, Gene Expression Omnibus (GEO), Online Mendelian Inheritance in Man (OMIM), the Molecular Modeling Database (MMDB), the Conserved Domain Database (CDD), and the Conserved Domain Architecture Retrieval Tool (CDART). Augmenting many of the Web applications are custom implementations of the BLAST program optimized to search specialized data sets. All of the resources can be accessed through the NCBI home page at: http://www.ncbi.nlm.nih.gov.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                3 February 2017
                13 February 2017
                April 2017
                13 August 2017
                : 49
                : 4
                : 515-526
                Affiliations
                [1 ]Department of Genome Sciences, University of Washington, Seattle, WA, USA
                [2 ]Department of forensic medicine and Institute of Brain Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
                [3 ]The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
                [4 ]Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands
                [5 ]Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands
                [6 ]Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
                [7 ]Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
                [8 ]Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA
                [9 ]Centre for Human Genetics, KU Leuven and Leuven Autism Research (LAuRes), Leuven, Belgium
                [10 ]Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands
                [11 ]Robinson Research Institute and the University of Adelaide at the Women’s and Children’s Hospital, North Adelaide, Australia
                [12 ]SA Pathology, Adelaide, Australia
                [13 ]South Australian Clinical Genetics Service, SA Pathology (at Women’s and Children’s Hospital), Adelaide, Australia, Australia
                [14 ]South Australian Health and Medical Research Institute, Adelaide, Australia
                [15 ]Center for Molecular Studies, J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, USA
                [16 ]Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
                [17 ]Unit of Pediatrics & Medical Genetics
                [18 ]Unit of Neurology, IRCCS Associazione Oasi Maria Santissima, Troina, Italy
                [19 ]UCSD, Autism Center of Excellence, La Jolla, CA, USA
                [20 ]MIND Institute and the University of California Davis School of Medicine, Sacramento, CA, USA
                [21 ]Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Melbourne, Victoria, Australia
                [22 ]Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia
                [23 ]The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
                [24 ]Victorian Clinical Genetics Services, Parkville, Victoria, Australia
                [25 ]Bruce Lefroy Centre for Genetic Health Research, Murdoch Children’s Research Institute, Parkville, Victoria, Australia
                [26 ]Department of Biochemistry and Molecular Medicine, University of California at Davis, Davis, CA, USA
                [27 ]Howard Hughes Medical Institute, Seattle, WA, USA
                Author notes
                Corresponding author: Evan E. Eichler, Ph.D., Department of Genome Sciences, University of Washington School of Medicine, Foege S-413A, Box 355065, 3720 15th Ave NE, Seattle, WA 98195-5065, eee@ 123456gs.washington.edu , Tel 001-(1)2066857336, Fax 001-(1)2062215795
                [α]

                Present address: Department of Pharmacology, Creighton University School of Medicine, Omaha, NE, USA.

                [Ψ]

                Shared first authors.

                [β]

                Authors contributed equally.

                Article
                NIHMS846201
                10.1038/ng.3792
                5374041
                28191889
                23c6de2c-a177-45c3-9347-f396622463be

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