title: Evidence for involvement of GNB1L in autism.
abstract: Structural variations in the chromosome 22q11.2 region mediated by nonallelic homologous recombination result in 22q11.2 deletion (del22q11.2) and 22q11.2 duplication (dup22q11.2) syndromes. The majority of del22q11.2 cases have facial and cardiac malformations, immunologic impairments, specific cognitive profile and increased risk for schizophrenia and autism spectrum disorders (ASDs). The phenotype of dup22q11.2 is frequently without physical features but includes the spectrum of neurocognitive abnormalities. Although there is substantial evidence that haploinsufficiency for TBX1 plays a role in the physical features of del22q11.2, it is not known which gene(s) in the critical 1.5 Mb region are responsible for the observed spectrum of behavioral phenotypes. We identified an individual with a balanced translocation 46,XY,t(1;22)(p36.1;q11.2) and a behavioral phenotype characterized by cognitive impairment, autism, and schizophrenia in the absence of congenital malformations. Using somatic cell hybrids and comparative genomic hybridization (CGH) we mapped the chromosome-22 breakpoint within intron 7 of the GNB1L gene. Copy number evaluations and direct DNA sequencing of GNB1L in 271 schizophrenia and 513 autism cases revealed dup22q11.2 in two families with autism and private GNB1L missense variants in conserved residues in three families (P = 0.036). The identified missense variants affect residues in the WD40 repeat domains and are predicted to have deleterious effects on the protein. Prior studies provided evidence that GNB1L may have a role in schizophrenia. Our findings support involvement of GNB1L in ASDs as well.
authors.affiliation: Department of Medicine (Medical Genetics), University of Washington, Seattle, Washington 98195-7720, USA.
authors.forename: Ying-Zhang
authors.initials: YZ
authors.lastname: Chen
authors.forename: Mark
authors.initials: M
authors.lastname: Matsushita
authors.forename: Santhosh
authors.initials: S
authors.lastname: Girirajan
authors.forename: Mark
authors.initials: M
authors.lastname: Lisowski
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sun
authors.forename: Youngmee
authors.initials: Y
authors.lastname: Sul
authors.forename: Raphael
authors.initials: R
authors.lastname: Bernier
authors.forename: Annette
authors.initials: A
authors.lastname: Estes
authors.forename: Geraldine
authors.initials: G
authors.lastname: Dawson
authors.forename: Nancy
authors.initials: N
authors.lastname: Minshew
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Shellenberg
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Debby W
authors.initials: DW
authors.lastname: Tsuang
authors.forename: Ming T
authors.initials: MT
authors.lastname: Tsuang
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Wijsman
authors.forename: Wendy H
authors.initials: WH
authors.lastname: Raskind
authors.forename: Zoran
authors.initials: Z
authors.lastname: Brkanac
mesh_terms: D000293:Adolescent; D001321:Autistic Disorder / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D019457:Chromosome Breakage; D056915:DNA Copy Number Variations / Q000235:genetics; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D020440:Gene Duplication / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007621:Karyotyping; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D014178:Translocation, Genetic
chemical_list: C434113:GNB1L protein, human; D047908:Intracellular Signaling Peptides and Proteins
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