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Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatirc disorders
  1. David T. Miller (david.miller2{at}childrens.harvard.edu)
  1. Children's Hospital Boston, United States
    1. Yiping Shen (yiping.shen{at}childrens.harvard.edu)
    1. Children's Hospital Boston, United States
      1. Lauren A. Weiss (laweiss{at}chgr.mgh.harvard.edu)
      1. Massachusetts General Hospital, United States
        1. Joshua Korn (joshkorn{at}gmail.com)
        1. Massachusetts General Hospital, United States
          1. Irina Anselm (irina.anselm{at}childrens.harvard.edu)
          1. Children's Hospital Boston, United States
            1. Carolyn Bridgemohan (carolyn.bridgemohan{at}childrens.harvard.edu)
            1. Children's Hospital Boston, United States
              1. Gerald F. Cox (gerald.cox{at}genzyme.com)
              1. Genzyme Corporation, United States
                1. Hope Dickinson (hope.dickinson{at}childrens.harvard.edu)
                1. Children's Hospital Boston, United States
                  1. Jennifer Gentile (jennifer.gentile{at}childrens.harvard.edu)
                  1. Children's Hospital Boston, United States
                    1. David J. Harris (vid.harris2{at}childrens.harvard.edu)
                    1. Children's Hospital Boston, United States
                      1. Vijay Hegde (vijay.hegde{at}childrens.harvard.edu)
                      1. Children's Hospital Boston, United States
                        1. Rachel Hundley (rachel.hundley{at}childrens.harvard.edu)
                        1. Children's Hospital Boston, United States
                          1. Omar Khwaja (omar.khwaja{at}childrens.harvard.edu)
                          1. Children's Hospital Boston, United States
                            1. Sanjeev Kothare (sanjeev.kothare{at}childrens.harvard.edu)
                            1. Children's Hospital Boston, United States
                              1. Christina Luedke (christina.luedke{at}childrens.harvard.edu)
                              1. Children's Hospital Boston, United States
                                1. Ramzi Nasir (ramzi.nasir{at}childrens.harvard.edu)
                                1. Children's Hospital Boston, United States
                                  1. Annapurna Poduri (annapurna.poduri{at}childrens.harvard.edu)
                                  1. Children's Hospital Boston, United States
                                    1. Kiran Prasad (kiran.prasad{at}childrens.harvard.edu)
                                    1. Children's Hospital Boston, United States
                                      1. Peter Raffalli (peter.raffalli{at}childrens.harvard.edu)
                                      1. Children's Hospital Boston, United States
                                        1. Ann Reinhard (ann.reinhard{at}childrens.harvard.edu)
                                        1. Children's Hospital Boston, United States
                                          1. Sharon E. Smith (sharon.smith{at}genzyme.com)
                                          1. Genzyme Corporation, United States
                                            1. Magdi Sobeih (magdi.sobeih{at}childrens.harvard.edu)
                                            1. Children's Hospital Boston, United States
                                              1. Janet Soul (janet.soul{at}childrens.harvard.edu)
                                              1. Children's Hospital Boston, United States
                                                1. Joan Stoler (joan.stoler{at}childrens.harvard.edu)
                                                1. Children's Hospital Boston, United States
                                                  1. Masanori. Takeoka (masanori.takeoka{at}childrens.harvard.edu)
                                                  1. Children's Hospital Boston, United States
                                                    1. Wen-Hann Tan (wen-hann.tan{at}childrens.harvard.edu)
                                                    1. Children's Hospital Boston, United States
                                                      1. Joseph Thakuria (joseph.thakuria{at}childrens.harvard.edu)
                                                      1. Children's Hospital Boston, United States
                                                        1. Peter Wolff (peter.wolff{at}childrens.harvard.edu)
                                                        1. Children's Hospital Boston, United States
                                                          1. Roman Yusupov (roman.yusupov{at}childrens.harvard.edu)
                                                          1. Children's Hospital Boston, United States
                                                            1. James F. Gusella (gusella{at}helix.mgh.harvard.edu)
                                                            1. Massachusetts General Hospital, United States
                                                              1. Mark J. Daly (mjdaly{at}chgr.mgh.harvard.edu)
                                                              1. Massachusetts General Hospital, United States
                                                                1. Bai-Lin Wu (bai-lin.wu{at}childrens.harvard.edu)
                                                                1. Children's Hospital Boston, United States

                                                                  Abstract

                                                                  Background: Segmental duplications at breakpoints (BP4-BP5) of chromosome 15q13.2q13.3 mediate a recurrent genomic imbalance syndrome associated with mental retardation, epilepsy, and/or EEG abnormalities.

                                                                  Patients: DNA samples from 1,445 unrelated patients submitted consecutively for clinical array comparative genomic hybridisation (CGH) testing at Children’s Hospital Boston and DNA samples from 1,441 individuals with Autism from 751 families in the Autism Genetic Resource Exchange (AGRE) repository.

                                                                  Results: We report the clinical features of five patients with a BP4-BP5 deletion, 3 with a BP4-BP5 duplication, and 2 with an overlapping but smaller duplication identified by whole genome high resolution oligonucleotide array CGH. These BP4-BP5 deletion cases exhibit minor dysmorphic features, significant expressive language deficits, and a spectrum of neuropsychiatric impairments that include autism spectrum disorder, ADHD, anxiety disorder, and mood disorder. Cognitive impairment varied from moderate mental retardation to normal IQ with learning disability. BP4-BP5 covers ~1.5Mb (chr15:28.719-30.298Mb) and includes 6 reference genes and 1 miRNA gene, while the smaller duplications cover ~500 kb (chr15:28.902-29.404 Mb and contain 3 reference genes and one miRNA gene. The BP4-BP5 deletion and duplication events span CHRNA7, a candidate gene for seizures. However, none of these individuals reported here has epilepsy, although one has an abnormal EEG.

                                                                  Conclusions: The phenotype of chromosome 15q13.2q13.3 BP4-BP5 microdeletion/duplication syndrome may include features of autism spectrum disorder, a variety of neuropsychiatric disorders, and cognitive impairment. Recognition of this broader phenotype has implications for clinical diagnostic testing and efforts to understand the underlying etiology of this syndrome.

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