Date Published: January 16, 2012
Publisher: Wiley Subscription Services, Inc., A Wiley Company
Author(s): 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.
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. © 2011 Wiley Periodicals, Inc.
The chromosome 22q11.2 genomic region harbors four low-copy repeats that make it susceptible to nonallelic homologous recombination that is responsible for the 22q11 deletion (del22q11.2) and duplication (dup22q11.2) syndromes [Stankiewicz and Lupski 2002]. Del22q11.2 is the most common genomic disorder, with a frequency of 1 in 4,000 to 1 in 7,000 births [Botto et al., 2003; Oskarsdottir et al., 2004]. This complex disorder has been called velocardiofacial syndrome (VCFS) [MIM 192430] for its associated facial dysmorphism, palatal clefting or insufficiency, and conotruncal heart abnormalities, or DiGeorge sequence (DGS) [MIM 188400] when the immune system and parathyroid function are compromised. Del22q11.2 also has a prominent cognitive and behavioral component [Murphy 2005]. Individuals with del22q11.2 have a lower IQ than expected and a complex psychoeducational profile characterized by language impairment and higher verbal than performance IQ [Moss et al., 1999; Antshel et al., 2008]. Del22q11.2 greatly increases the risk for psychiatric disorders. An autism spectrum disorder (ASD) is diagnosed in as many as 50% and schizophrenia or related psychosis develops in approximately one-third of individuals with del22q11.2 [Murphy et al., 1999; Fine et al., 2005; Vorstman et al., 2006; Antshel et al., 2007; Niklasson et al., 2009]. Conversely, the microdeletion has been found in approximately 1–3% of adults with schizophrenia and with much higher frequencies in the subsets with childhood onset, making del22q11.2 the most frequent genetic cause of schizophrenia in the general population [Yan et al., 1998; Wiehahn et al., 2004; Horowitz et al., 2005]. Complex neurodevelopmental phenotypes also characterize the newly recognized reciprocal dup22q11.2 syndrome [MIM 608363]. The phenotype of the individuals with dup22q11.2 is exceedingly diverse—some individuals have no apparent abnormalities, but others manifest phenotypes ranging from congenital malformations reminiscent of del22q11.2 to behavioral disorders including intellectual disability, ASD, and learning disorders [Mukaddes and Herguner, 2007; Ramelli et al., 2008; Lo-Castro et al., 2009], further supporting the importance of the 22q11.2 region in cognition and behavior.
There is increasing evidence that autism and schizophrenia are highly heterogeneous disorders on both phenotypic and genotypic levels [McClellan et al., 2007; Abrahams and Geschwind, 2008; Bassett et al., 2010; State, 2010]. Recent molecular studies have identified multiple risk factors for both disorders. For autism there is evidence for a pathogenic effect of missense mutations in a number of genes, including NLGN3 (MIM 300336) and NLGN4 (MIM 300427) [Jamain et al., 2003], NRXN1 (MIM 600565) [Kim et al., 2008], SHANK3 (MIM 606230) [Durand et al., 2007], SHANK2 (MIM 603290) [Berkel et al., 2010], and CNTNAP2 (MIM 604569) [Bakkaloglu et al., 2008]. In addition to the 22q11.2 region, recurrent deletions and duplications at 7q11.3, 15q11–q13, 16p11.2, and 17p11.2 have autism as a frequent phenotypic presentation [Cook and Scherer 2008; Stankiewicz and Lupski, 2010). None of these single gene mutations or CNVs account for more than a minority of autism cases. Similarly, for schizophrenia, the list of candidate genes and CNVs continues to increase [Bassett et al., 2010; Stankiewicz and Lupski, 2010]. To date, the cumulative results point to involvement of many genes and unknown environmental influences on the pathogeneses of autism and schizophrenia and the variability in their phenotypic expression.