Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders

Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Science (Impact Factor: 31.48). 11/2012; 338(6114). DOI: 10.1126/science.1227764
Source: PubMed

ABSTRACT Exome sequencing studies of autism spectrum disorders (ASDs) have identified many de novo mutations but few recurrently disrupted
genes. We therefore developed a modified molecular inversion probe method enabling ultra-low-cost candidate gene resequencing
in very large cohorts. To demonstrate the power of this approach, we captured and sequenced 44 candidate genes in 2446 ASD
probands. We discovered 27 de novo events in 16 genes, 59% of which are predicted to truncate proteins or disrupt splicing.
We estimate that recurrent disruptive mutations in six genes—CHD8, DYRK1A, GRIN2B, TBR1, PTEN, and TBL1XR1—may contribute to 1% of sporadic ASDs. Our data support associations between specific genes and reciprocal subphenotypes
(CHD8-macrocephaly and DYRK1A-microcephaly) and replicate the importance of a β-catenin–chromatin-remodeling network to ASD etiology.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Abnormal copy number of chromosomes, genes, or individual exons can have deleterious effects that lead to recognizable genetic disorders. Until recently, the traditional methods of karyotyping, fluorescence in situ hybridization, and rudimentary PCR-based assays were the only choices available to detect copy number abnormalities. The advent of chromosomal microarrays and next-generation sequencing has now dramatically improved our ability to detect deletions or duplications with superior resolution compared to that possible with previous methods. Each method has inherent properties and variations that provide advantages in detecting mutations in specific genomic environments, but those same properties can be limiting in other regions as well as in scalability. Improvements in bioinformatics algorithms predict a complete shift toward next-generation sequencing for detecting the entire range of copy number abnormalities, although microarray and other technologies will continue to be useful as confirmatory tests and for investigating complex structural rearrangements and non-unique sequences.
    06/2013; 1(2). DOI:10.1007/s40142-013-0013-7
  • [Show abstract] [Hide abstract]
    ABSTRACT: The last several years have seen unprecedented advances in deciphering the genetic etiology of autism spectrum disorders (ASDs). Heritability studies have repeatedly affirmed a contribution of genetic factors to the overall disease risk. Technical breakthroughs have enabled the search for these genetic factors via genome-wide surveys of a spectrum of potential sequence variations, from common single-nucleotide polymorphisms to essentially private chromosomal abnormalities. Studies of copy-number variation have identified significant roles for both recurrent and nonrecurrent large dosage imbalances, although they have rarely revealed the individual genes responsible. More recently, discoveries of rare point mutations and characterization of balanced chromosomal abnormalities have pinpointed individual ASD genes of relatively strong effect, including both loci with strong a priori biological relevance and those that would have otherwise been unsuspected as high-priority biological targets. Evidence has also emerged for association with many common variants, each adding a small individual contribution to ASD risk. These findings collectively provide compelling empirical data that the genetic basis of ASD is highly heterogeneous, with hundreds of genes capable of conferring varying degrees of risk, depending on their nature and the predisposing genetic alteration. Moreover, many genes that have been implicated in ASD also appear to be risk factors for related neurodevelopmental disorders, as well as for a spectrum of psychiatric phenotypes. While some ASD genes have evident functional significance, like synaptic proteins such as the SHANKs, neuroligins, and neurexins, as well as fragile x mental retardation-associated proteins, ASD genes have also been discovered that do not present a clear mechanism of specific neurodevelopmental dysfunction, such as regulators of chromatin modification and global gene expression. In its sum, the progress from genetic studies to date has been remarkable and increasingly rapid, but the interactive impact of strong-effect genetic lesions coupled with weak-effect common polymorphisms has not yet led to a unified understanding of ASD pathogenesis or explained its highly variable clinical expression. With an increasingly firm genetic foundation, the coming years will hopefully see equally rapid advances in elucidating the functional consequences of ASD genes and their interactions with environmental/experiential factors, supporting the development of rational interventions.
    Harvard Review of Psychiatry 22(2):65-75. DOI:10.1097/HRP.0000000000000002 · 2.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Transducin (beta)-like 1X related protein 1 (TBL1XR1/TBLR1) is an integral subunit of the NCoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoic acid and thyroid hormone receptors) repressor complexes. It is an evolutionally conserved protein that shares high similarity across all species. TBL1XR1 is essential for transcriptional repression mediated by unliganded nuclear receptors (NRs) and othe regulated transcription factors (TFs). However, it can also act as a transcription activator through the recruitment of the ubiquitin-conjugating/19S proteasome complex that mediates the exchange of corepressors for coactivators. TBL1XR1 is required for the activation of multiple intracellular signaling pathways. TBL1XR1 germline mutations and recurrent mutations are linked to intellectual disability. Upregulation of TBL1XR1 is observed in a variety of solid tumors, which is associated with advanced tumor stage, metastasis and poor prognosis. A variety of genomic alterations, such as translocation, deletion and mutation have been identified in many types of neoplasms. Loss of TBL1XR1 in B-lymphoblastic leukemia disrupts glucocorticoid receptor recruitment to chromatin and results in glucocorticoid resistance. However, the mechanisms of other types of genomic changes in tumorogenesis are still not clear. A pre-clinical study has shown that the disruption of the interaction between TBL1X and β-catenin using a small molecule can inhibit the growth of AML stem and blast cells both in vitro and in vivo. These findings shed light on the therapeutic potentials of targeting TBL1XR1 related proteins in cancer treatment.
Show more