title: Clinical and molecular characterization of three genomic rearrangements at chromosome 22q13.3 associated with autism spectrum disorder.
abstract: Chromosome 22q13 is a hot region of genomic rearrangements that may result in deletion, duplication, and translocation, and that may lead to neurodevelopmental disorders in affected patients.
  
  
  
  We carried out an array-based comparative genomic hybridization analysis to detect copy number variations (CNVs) of genomic DNA in patients with autism spectrum disorders (ASD) who were consecutively recruited into our molecular genetic study of ASD. Karyotyping, fluorescent in-situ hybridization analysis, and real time-quantitative PCR were used for validation tests.
  
  
  
  We completed a genome-wide CNV analysis of 335 patients with ASD from Taiwan. Three unrelated male patients were found to carry three different CNVs at 22q13.3, respectively, including a de novo terminal deletion of ∼106 kb at 22q13.33, a de novo interstitial duplication of ∼1.8 Mb at 22q13.32-q13.33, and a microdeletion of ∼147 kb at 22q13.33. These three CNVs all involved the dosage change of the SHANK3 gene. The last patient also carried a genomic duplication of ∼3.86 Mb at 19q13.42-q13.4 in addition to a microdeletion of ∼147 kb at 22q13.33. His younger sister also carried these two CNVs, but she had developmental delay and other neurological deficits without ASD. These two CNVs were transmitted from their unaffected father, who carried a balanced translocation between chromosome 22q and 19q.
  
  
  
  Our data support that recurrent genomic rearrangements at 22q13.3 are part of the genetic landscape of ASD in our patients and changes in SHANK3 dosage are associated with neurodevelopmental disorders. However, the clinical symptoms of patients with 22q13.3 rearrangements can vary depending on other genetic and nongenetic factors, not limited to genes involved in CNVs in this region.
authors.affiliation: aDepartment of Psychiatry, Chang Gung Memorial Hospital-Linkou Medical Center bGraduate Institute of Biomedicine, Chang Gung University, Taoyuan cDepartment of Psychiatry, College of Medicine, National Taiwan University Hospital dDepartment of Life Sciences, Institute of Genome Sciences, National Yang-Ming University eGraduate Institute of Brain and Mind Sciences, National Taiwan University, Taipei fGraduate Institute of Clinical Medicine, National Taiwan University, Taipei gCenter for Medical Genetics, Tzu-Chi General Hospital, Hualien, Taiwan.
authors.forename: Chia-Hsiang
authors.initials: CH
authors.lastname: Chen
authors.forename: Hsin-I
authors.initials: HI
authors.lastname: Chen
authors.forename: Hsiao-Mei
authors.initials: HM
authors.lastname: Liao
authors.forename: Yann-Jang
authors.initials: YJ
authors.lastname: Chen
authors.forename: Jye-Siung
authors.initials: JS
authors.lastname: Fang
authors.forename: Kuei-Fang
authors.initials: KF
authors.lastname: Lee
authors.forename: Susan Shur-Fen
authors.initials: SS
authors.lastname: Gau
mesh_terms: D000293:Adolescent; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics*; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D055028:Comparative Genomic Hybridization / Q000379:methods; D004247:DNA; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D023281:Genomics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D013624:Taiwan
chemical_list: D009419:Nerve Tissue Proteins; C492357:SHANK3 protein, human; D004247:DNA