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      Delineating the psychiatric and behavioral phenotype of recurrent 2q13 deletions and duplications

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      1 , , 1 , 2 , 3 , 4 , 2 , 2 , 5 , 6 , 7 , 8 , 9 , 10 , 2 , 11 , 12 , 2 , 13 , 11 , 14 , 15 , 16 , 17 , 3 , 6 , 8 , 18 , 19 , 5 , 6 , 1 , 20 , 21 , 1
      American Journal of Medical Genetics
      John Wiley and Sons Inc.
      attention deficit hyperactivity disorder, autism spectrum disorders, copy number variants, developmental delay, intellectual disabilities

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          Abstract

          Recurrent deletions and duplications at the 2q13 locus have been associated with developmental delay (DD) and dysmorphisms. We aimed to undertake detailed clinical characterization of individuals with 2q13 copy number variations (CNVs), with a focus on behavioral and psychiatric phenotypes. Participants were recruited via the Unique chromosomal disorder support group, U.K. National Health Service Regional Genetics Centres, and the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) database. A review of published 2q13 patient case reports was undertaken to enable combined phenotypic analysis. We present a new case series of 2q13 CNV carriers (21 deletion, 4 duplication) and the largest ever combined analysis with data from published studies, making a total of 54 deletion and 23 duplication carriers. DD/intellectual disabilities was identified in the majority of carriers (79% deletion, 70% duplication), although in the new cases 52% had an IQ in the borderline or normal range. Despite the median age of the new cases being only 9 years, 64% had a clinical psychiatric diagnosis. Combined analysis found attention deficit hyperactivity disorder (ADHD) to be the most frequent diagnosis (48% deletion, 60% duplication), followed by autism spectrum disorders (33% deletion, 17% duplication). Aggressive (33%) and self‐injurious behaviors (33%) were also identified in the new cases. CNVs at 2q13 are typically associated with DD with mildly impaired intelligence, and a high rate of childhood psychiatric diagnoses—particularly ADHD. We have further characterized the clinical phenotype related to imbalances of the 2q13 region and identified it as a region of interest for the neurobiological investigation of ADHD.

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          Most cited references23

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          A recurrent 16p12.1 microdeletion suggests a two-hit model for severe developmental delay

          We report the identification of a recurrent 520-kbp 16p12.1 microdeletion significantly associated with childhood developmental delay. The microdeletion was detected in 20/11,873 cases vs. 2/8,540 controls (p=0.0009, OR=7.2) and replicated in a second series of 22/9,254 cases vs. 6/6,299 controls (p=0.028, OR=2.5). Most deletions were inherited with carrier parents likely to manifest neuropsychiatric phenotypes (p=0.037, OR=6). Probands were more likely to carry an additional large CNV when compared to matched controls (10/42 cases, p=5.7×10-5, OR=6.65). Clinical features of cases with two mutations were distinct from and/or more severe than clinical features of patients carrying only the co-occurring mutation. Our data suggest a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity suggests that this two-hit model may be more generally applicable to neuropsychiatric disease.
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            TheRCommander: A Basic-Statistics Graphical User Interface toR

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              Estimates of penetrance for recurrent pathogenic copy-number variations

              Purpose: Although an increasing number of copy-number variations are being identified as susceptibility loci for a variety of pediatric diseases, the penetrance of these copy-number variations remains mostly unknown. This poses challenges for counseling, both for recurrence risks and prenatal diagnosis. We sought to provide empiric estimates for penetrance for some of these recurrent, disease-susceptibility loci. Methods: We conducted a Bayesian analysis, based on the copy-number variation frequencies in control populations (n = 22,246) and in our database of >48,000 postnatal microarray-based comparative genomic hybridization samples. The background risk for congenital anomalies/developmental delay/intellectual disability was assumed to be ~5%. Copy-number variations studied were 1q21.1 proximal duplications, 1q21.1 distal deletions and duplications, 15q11.2 deletions, 16p13.11 deletions, 16p12.1 deletions, 16p11.2 proximal and distal deletions and duplications, 17q12 deletions and duplications, and 22q11.21 duplications. Results: Estimates for the risk of an abnormal phenotype ranged from 10.4% for 15q11.2 deletions to 62.4% for distal 16p11.2 deletions. Conclusion: This model can be used to provide more precise estimates for the chance of an abnormal phenotype for many copy-number variations encountered in the prenatal setting. By providing the penetrance, additional, critical information can be given to prospective parents in the genetic counseling session.
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                Author and article information

                Contributors
                k.wolfe@ucl.ac.uk
                Journal
                Am J Med Genet B Neuropsychiatr Genet
                Am. J. Med. Genet. B Neuropsychiatr. Genet
                10.1002/(ISSN)1552-485X
                AJMG
                American Journal of Medical Genetics
                John Wiley and Sons Inc. (Hoboken )
                1552-4841
                1552-485X
                31 March 2018
                June 2018
                : 177
                : 4 ( doiID: 10.1002/ajmg.b.v177.4 )
                : 397-405
                Affiliations
                [ 1 ] Molecular Psychiatry Laboratory, Division of Psychiatry University College London London United Kingdom
                [ 2 ] Medical Genetics Unit, Medical Genetics Laboratory Bambino Gesù Pediatric Hospital, IRCCS Rome Italy
                [ 3 ] Institut de génétique médicale, CHU Lille Lille France
                [ 4 ] Nottinghamshire Healthcare NHS Foundation Trust Nottingham United Kingdom
                [ 5 ] Service de génétique clinique, CHU Lille Lille France
                [ 6 ] EA7364, RADEME, Université de Lille Lille France
                [ 7 ] Centre de génétique chromosomique, Hopital Saint‐Vincent de Paul Lille France
                [ 8 ] Kennedy Center, Department of Clinical Genetics Copenhagen University Hospital, Rigshospitalet Copenhagen Denmark
                [ 9 ] Hunter Genetics Waratah New South Wales Australia
                [ 10 ] University of Newcastle Callaghan New South Wales Australia
                [ 11 ] North East Thames Regional Genetics Service Laboratory London United Kingdom
                [ 12 ] Service de Cytogénétique, Plateau technique de Biologie CHU Dijon France
                [ 13 ] Centre de référence Anomalies du développement et Syndromes malformatifs, FHU TRANSLAD CHU Dijon France
                [ 14 ] Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Western Bank Sheffield United Kingdom
                [ 15 ] King's College London, Florence Nightingale Faculty of Nursing and Midwifery London United Kingdom
                [ 16 ] Genomics England, Dawson Hall, Charterhouse Square London United Kingdom
                [ 17 ] Information Officer, Unique – The Rare Chromosome Disorder Support Group (www.rarechromo.org), The Stables, Station Road West Oxted, Surrey United Kingdom
                [ 18 ] Center for Medical Genetics Ghent University Hospital Ghent Belgium
                [ 19 ] Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands
                [ 20 ] Department of Forensic and Neurodevelopmental Science Institute of Psychiatry, Psychology and Neuroscience, Kings College London London United Kingdom
                [ 21 ] Behavioural and Brain Sciences Unit Institute of Child Health, University College London London United Kingdom
                Author notes
                [*] [* ] Correspondence

                Kate Wolfe, Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, Rockefeller Building, Gower Street, London WC1E 6BT, United Kingdom.

                Email: k.wolfe@ 123456ucl.ac.uk

                Author information
                http://orcid.org/0000-0003-0044-5379
                http://orcid.org/0000-0001-9770-444X
                Article
                AJMGB32627
                10.1002/ajmg.b.32627
                6001478
                29603867
                f86a242e-02cb-474e-ae2b-415329a651f2
                © 2018 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 January 2018
                : 01 March 2018
                Page count
                Figures: 4, Tables: 1, Pages: 9, Words: 6245
                Funding
                Funded by: Baily Thomas Charitable Fund
                Award ID: TRUST/RNA/AC/KW/3087/1
                Funded by: Medical Research Council
                Award ID: PhD studentship—MR/K501268/1
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                ajmgb32627
                June 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.1.1 mode:remove_FC converted:14.06.2018

                Genetics
                attention deficit hyperactivity disorder,autism spectrum disorders,copy number variants,developmental delay,intellectual disabilities

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