Evidence for involvement of GNB1L in autism

Ying Zhang Chen, Mark Matsushita, Santhosh Girirajan, Mark Lisowski, Elizabeth Sun, Youngmee Sul, Raphael Bernier, Annette Estes, Geraldine Dawson, Nancy Minshew, Gerard D. Shellenberg, Evan E. Eichler, Mark J. Rieder, Deborah A. Nickerson, Debby W. Tsuang, Ming T. Tsuang, Ellen M. Wijsman, Wendy H. Raskind, Zoran Brkanac

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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 1.5Mb 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.

Original languageEnglish (US)
Pages (from-to)61-71
Number of pages11
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume159 B
Issue number1
DOIs
StatePublished - Jan 2012

All Science Journal Classification (ASJC) codes

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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