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.

FIG. 1

Karyotype showing the balanced translocation t(1;22)(p36.1;q11.2) in the proband and other members of his family. Arrows indicate derivative chromosomes 1 and 22.

FIG. 2

Fine mapping of the chromosome 22 translocation breakpoint. The derivative chromosome 22 was differentially labeled with Cy3-dCTP, derivative chromosome 1 was labeled with Cy5-dCTP and both were hybridized to chromosome 22 specific oligonucleotide array (NimbleGen HG 18 Chr22 design). The hybridization localized the breakpoint at sufficiently high resolution (A) to enable PCR based breakpoint cloning (B). The chromosome 22 breakpoint is between 18,167, 843-18, 167,854 bp, within intron 7 of the GNB1L gene, and encompasses a 10 bp deletion shown in lower case (tcttctctgc).

FIG. 3

Schematic of GNB1L and corresponding protein and transmission of GNB1L variants in families with autism. A: The chromosome 22 translocation breakpoint lies in intron 7. The locations of the three unique variants found in ASD in the WD40 motifs are indicated. B: Affected individuals in all families have a diagnosis of autism or ASD, indicated by black fill. Up-arrow indicates an elevated BPASS social motivation and range of interest/flexibility scores; scores have a direct correlation with symptoms of ASD such that high scores are abnormal.

FIG. 4

Identification of GNB1L duplication and transmission patterns in two families with autism. Affected individuals in the pedigrees have a diagnosis of autism or ASD, indicated by black fill. Up-arrow indicates elevated BPASS social motivation and range of interest/flexibility scores. (+) indicates 22q11.2 duplication shown as increased copy number by TaqMan and CGH.