title: Copy number variants analysis in a cohort of isolated and syndromic developmental delay/intellectual disability reveals novel genomic disorders, position effects and candidate disease genes.
abstract: BACKGROUND
  Array-comparative genomic hybridization (array-CGH) is a widely used technique to detect copy number variants (CNVs) associated with developmental delay/intellectual disability (DD/ID).
  
  
  OBJECTIVE
  Identification of genomic disorders in DD/ID.
  
  
  METHODS
  We performed a comprehensive array-CGH investigation of 1,015 consecutive cases with DD/ID and combined literature mining, genetic evidence, evolutionary constraint scores, and functional information in order to assess the pathogenicity of the CNVs.
  
  
  RESULTS
  We identified non-benign CNVs in 29% of patients. Amongst the pathogenic variants (11%), detected with a yield consistent with the literature, we found rare genomic disorders and CNVs spanning known disease genes. We further identified and discussed 51 cases with likely pathogenic CNVs spanning novel candidate genes, including genes encoding synaptic components and/or proteins involved in corticogenesis. Additionally, we identified two deletions spanning potential Topological Associated Domain (TAD) boundaries probably affecting the regulatory landscape.
  
  
  CONCLUSIONS
  We show how phenotypic and genetic analyses of array-CGH data allow unraveling complex cases, identifying rare disease genes, and revealing unexpected position effects.
authors.affiliation: University of Torino, Department of Medical Sciences, Turin, Italy.|Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Turin, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Di Gregorio
authors.affiliation: Department of Public Health and Pediatrics, University of Torino, Turin, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Riberi
authors.affiliation: Department of Public Health and Pediatrics, University of Torino, Turin, Italy.
authors.forename: E F
authors.initials: EF
authors.lastname: Belligni
authors.affiliation: Department of Public Health and Pediatrics, University of Torino, Turin, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Biamino
authors.affiliation: Research Group Mundlos, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Spielmann
authors.affiliation: Computational Biology Unit, Molecular Biotechnology Center (MBC), Turin, Italy.|Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy.
authors.forename: U
authors.initials: U
authors.lastname: Ala
authors.affiliation: University of Torino, Department of Medical Sciences, Turin, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Calcia
authors.affiliation: Neuropsichiatria Infantile, Martini Hospital, ASL TO1, Turin, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Bagnasco
authors.affiliation: University of Torino, Department of Medical Sciences, Turin, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Carli
authors.affiliation: Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Turin, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Gai
authors.affiliation: Department of Health Sciences, Laboratory of Genetics, University of Eastern Piedmont and Interdisciplinary Research Center of Autoimmune Diseases, Novara, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Giordano
authors.affiliation: SOC Pediatria, Castelli Hospital, Verbania, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Guala
authors.affiliation: Mental Health Department, ASL TO2, Adult Autism Center, Turin, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Keller
authors.affiliation: Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Turin, Italy.|Medical Genetics, San Luigi Gonzaga University Hospital, Orbassano (TO), Italy.
authors.forename: G
authors.initials: G
authors.lastname: Mandrile
authors.affiliation: Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Turin, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Arduino
authors.affiliation: Molecular Biology and Genetics Unit, Santa Croce e Carle Hospital, Cuneo, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Maffè
authors.affiliation: Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Turin, Italy.
authors.forename: V G
authors.initials: VG
authors.lastname: Naretto
authors.affiliation: Molecular Biology and Genetics Unit, Santa Croce e Carle Hospital, Cuneo, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Sirchia
authors.affiliation: Pediatrics, Santa Croce e Carle Hospital, Cuneo, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Sorasio
authors.affiliation: Molecular Biology and Genetics Unit, Santa Croce e Carle Hospital, Cuneo, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Ungari
authors.affiliation: Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Turin, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Zonta
authors.affiliation: Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Turin, Italy.|Department of Health Sciences, Laboratory of Genetics, University of Eastern Piedmont and Interdisciplinary Research Center of Autoimmune Diseases, Novara, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Zacchetti
authors.affiliation: Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Turin, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Talarico
authors.affiliation: Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Turin, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Pappi
authors.affiliation: University of Torino, Department of Medical Sciences, Turin, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Cavalieri
authors.affiliation: University of Torino, Department of Medical Sciences, Turin, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Giorgio
authors.affiliation: University of Torino, Department of Medical Sciences, Turin, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Mancini
authors.affiliation: University of Torino, Department of Medical Sciences, Turin, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Ferrero
authors.affiliation: University of Torino, Department of Medical Sciences, Turin, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Brussino
authors.affiliation: Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Turin, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Savin
authors.affiliation: Department of Neuropsychiatry, University of Torino, Turin, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Gandione
authors.affiliation: Medical Genetics, San Luigi Gonzaga University Hospital, Orbassano (TO), Italy.|Department of Clinical and Biological Sciences, University of Torino, Turin, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Pelle
authors.affiliation: Medical Genetics, San Luigi Gonzaga University Hospital, Orbassano (TO), Italy.|Department of Clinical and Biological Sciences, University of Torino, Turin, Italy.
authors.forename: D F
authors.initials: DF
authors.lastname: Giachino
authors.affiliation: Medical Genetics, San Luigi Gonzaga University Hospital, Orbassano (TO), Italy.|Department of Clinical and Biological Sciences, University of Torino, Turin, Italy.
authors.forename: M
authors.initials: M
authors.lastname: De Marchi
authors.affiliation: Laboratory of Molecular Genetics, Città della Salute e della Scienza University Hospital, Turin, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Restagno
authors.affiliation: Computational Biology Unit, Molecular Biotechnology Center (MBC), Turin, Italy.|Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Provero
authors.affiliation: Department of Public Health and Pediatrics, University of Torino, Turin, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cirillo Silengo
authors.affiliation: Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Turin, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Grosso
authors.affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York.|Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.|Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.|Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: J D
authors.initials: JD
authors.lastname: Buxbaum
authors.affiliation: Molecular Biology and Genetics Unit, Santa Croce e Carle Hospital, Cuneo, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Pasini
authors.affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York.|Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: S
authors.initials: S
authors.lastname: De Rubeis
authors.affiliation: University of Torino, Department of Medical Sciences, Turin, Italy.|Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Turin, Italy.
authors.forename: A
authors.identifier: http://orcid.org/0000-0002-8318-7231
authors.initials: A
authors.lastname: Brusco
authors.affiliation: Department of Public Health and Pediatrics, University of Torino, Turin, Italy.
authors.forename: G B
authors.initials: GB
authors.lastname: Ferrero
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D055012:Chromosomal Position Effects / Q000235:genetics; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics* / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D023281:Genomics; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008297:Male; D010375:Pedigree; D010641:Phenotype; D017384:Sequence Deletion / Q000235:genetics; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C550332:MBD5 protein, human
keywords: 
  CNV; array-CGH; autism spectrum disorder; developmental delay; genomic disorders; intellectual disability