title: Microduplications in an autism multiplex family narrow the region of susceptibility for developmental disorders on 15q24 and implicate 7p21.
abstract: Copy number variations (CNVs) play a crucial role in the intricate genetics of autism spectrum disorders. A region on chromosome 15q24 vulnerable to both deletions and duplications has been previously implicated in a range of phenotypes including autism, Asperger's syndrome, delayed development, and mild to severe mental retardation. Prior studies have delineated a minimal critical region of approximately 1.33 Mb. In this study, a multiplex autism family was evaluated for CNVs using genotyping data from the Illumina 1 M BeadChip and analyzed with the PennCNV algorithm. Variants were then identified that co-segregate with autism features in this family. Here, we report autistic first cousins who carry two microduplications concordant with disease. Both duplications were inherited maternally and found to be identical by descent. The first is an approximately 10,000 base pair microduplication within the minimal region on 15q24 that falls across a single gene, ubiquitin-like 7. This is the smallest duplication in the region to result in a neuropsychiatric disorder, potentially narrowing the critical region for susceptibility to developmental and autism spectrum disorders. The second is a novel, 352 kb tandem duplication on 7p21 that replicates part of the neurexophilin 1 and islet cell autoantigen 1 genes. The breakpoint junction falls within the intronic regions of these genes and demonstrates a microhomology of four base pairs. Each of these microduplications may contribute to the complex etiology of autism spectrum disorders.
authors.affiliation: John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Florida, USA.
authors.forename: Holly N
authors.initials: HN
authors.lastname: Cukier
authors.forename: Daria
authors.initials: D
authors.lastname: Salyakina
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Blankstein
authors.forename: Joycelyn L
authors.initials: JL
authors.lastname: Robinson
authors.forename: Stephanie
authors.initials: S
authors.lastname: Sacharow
authors.forename: Deqiong
authors.initials: D
authors.lastname: Ma
authors.forename: Harry H
authors.initials: HH
authors.lastname: Wright
authors.forename: Ruth K
authors.initials: RK
authors.lastname: Abramson
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Menon
authors.forename: Scott M
authors.initials: SM
authors.lastname: Williams
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cuccaro
authors.forename: John R
authors.initials: JR
authors.lastname: Gilbert
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
mesh_terms: D001324:Autoantigens / Q000235:genetics; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000209:etiology / Q000235:genetics*; D002884:Chromosomes, Human, Pair 15; D002897:Chromosomes, Human, Pair 7; D056915:DNA Copy Number Variations; D005190:Family; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D009479:Neuropeptides / Q000235:genetics; D014452:Ubiquitins / Q000235:genetics
chemical_list: D001324:Autoantigens; D006023:Glycoproteins; C087054:ICA1 protein, human; D009479:Neuropeptides; C479964:UBL7 protein, human; D014452:Ubiquitins; C112162:neurexophilin