Rare Complete Knockouts in Humans: Population Distribution and Significant Role in Autism Spectrum Disorders

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA
Neuron (Impact Factor: 15.05). 01/2013; 77(2):235-42. DOI: 10.1016/j.neuron.2012.12.029
Source: PubMed


To characterize the role of rare complete human knockouts in autism spectrum disorders (ASDs), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a 2-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (≤5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudoautosomal regions on the X chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together, these results provide compelling evidence that rare autosomal and X chromosome complete gene knockouts are important inherited risk factors for ASD.

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Available from: Stephan J Sanders, Apr 18, 2014
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    • "All ASD cases were ascertained using the Autism Diagnostic Interview—Revised (ADIR), the Autism Diagnostic Observation Schedule—Generic (ADOS), and the DSM-IV diagnosis of pervasive developmental disorder (Neale et al., 2012; Lim et al., 2013; Liu et al., 2013). Clinical assessment of families harboring either variant is dependent on which collection they belong to. "
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    ABSTRACT: Syntaxin 1 (STX1) is a presynaptic plasma membrane protein that coordinates synaptic vesicle fusion. STX1 also regulates the function of neurotransmitter transporters, including the dopamine (DA) transporter (DAT). The DAT is a membrane protein that controls DA homeostasis through the high-affinity re-uptake of synaptically released DA. We adopt newly developed animal models and state-of-the-art biophysical techniques to determine the contribution of the identified gene variants to impairments in DA neurotransmission observed in autism spectrum disorder (ASD). Here, we characterize two independent autism-associated variants in the genes that encode STX1 and the DAT. We demonstrate that each variant dramatically alters DAT function. We identify molecular mechanisms that converge to inhibit reverse transport of DA and DA-associated behaviors. These mechanisms involve decreased phosphorylation of STX1 at Ser14 mediated by casein kinase 2 as well as a reduction in STX1/DAT interaction. These findings point to STX1/DAT interactions and STX1 phosphorylation as key regulators of DA homeostasis. We determine the molecular identity and the impact of these variants with the intent of defining DA dysfunction and associated behaviors as possible complications of ASD.
    Full-text · Article · Feb 2015 · EBioMedicine
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    • "HTS has also been applied successfully to identify causal mutations in a number of different genetic models including those not previously amenable to analysis. This includes de novo germline mutations (epi4K Consortium et al. 2013; Jiang et al. 2013; Lim et al. 2013). Sporadic mutations benefit from the application of the trio approach, where variants inherited from the parents are eliminated to identify the novel mutations in the proband. "
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    ABSTRACT: High-throughput sequencing studies (HTS) have been highly successful in identifying the genetic causes of human disease, particularly those following Mendelian inheritance. Many HTS studies to date have been performed without utilizing available family relationships between samples. Here, we discuss the many merits and occasional pitfalls of using identity by descent information in conjunction with HTS studies. These methods are not only applicable to family studies but are also useful in cohorts of apparently unrelated, 'sporadic' cases and small families underpowered for linkage and allow inference of relationships between individuals. Incorporating familial/pedigree information not only provides powerful filtering options for the extensive variant lists that are usually produced by HTS but also allows valuable quality control checks, insights into the genetic model and the genotypic status of individuals of interest. In particular, these methods are valuable for challenging discovery scenarios in HTS analysis, such as in the study of populations poorly represented in variant databases typically used for filtering, and in the case of poor-quality HTS data.
    Full-text · Article · Aug 2014 · Human Genetics
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    • "Although CNV and exome sequencing studies suggest that some 10% of ASD subjects carry a de novo risk variant, demonstrating that de novo genetic variation has an important role in risk for an ASD phenotype, this mechanism is inconsistent with the widely recognized high heritability. Convincing statistical evidence for the role of rare recessive inherited variants in ASD risk comes from two recent studies that applied whole-exome sequencing to a cohort of consanguineous and/or multiplex families and to ASD cases using a population-based approach [8,9]. The contribution of recessive mutations to ASD heritability is supported by the success of homozygosity mapping to identify autism genes in consanguineous families [10], the use of homozygosity mapping as a powerful strategy for filtering whole-exome sequence data [11] and the identification that ASD probands display a much higher degree of haplotype sharing within overlapping homozygous regions compared to parental controls [12]. "
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    ABSTRACT: Background Autism spectrum disorder (ASD) is a highly heritable, neurodevelopmental condition showing extreme genetic heterogeneity. While it is well established that rare genetic variation, both de novo and inherited, plays an important role in ASD risk, recent studies also support a rare recessive contribution. Methods We identified a compound heterozygous deletion intersecting the CTNNA3 gene, encoding αT-catenin, in a proband with ASD and moderate intellectual disability. The deletion breakpoints were mapped at base-pair resolution, and segregation analysis was performed. We compared the frequency of CTNNA3 exonic deletions in 2,147 ASD cases from the Autism Genome Project (AGP) study versus the frequency in 6,639 controls. Western blot analysis was performed to get a quantitative characterisation of Ctnna3 expression during early brain development in mouse. Results The CTNNA3 compound heterozygous deletion includes a coding exon, leading to a putative frameshift and premature stop codon. Segregation analysis in the family showed that the unaffected sister is heterozygote for the deletion, having only inherited the paternal deletion. While the frequency of CTNNA3 exonic deletions is not significantly different between ASD cases and controls, no homozygous or compound heterozygous exonic deletions were found in a sample of over 6,000 controls. Expression analysis of Ctnna3 in the mouse cortex and hippocampus (P0-P90) provided support for its role in the early stage of brain development. Conclusion The finding of a rare compound heterozygous CTNNA3 exonic deletion segregating with ASD, the absence of CTNNA3 homozygous exonic deletions in controls and the high expression of Ctnna3 in both brain areas analysed implicate CTNNA3 in ASD susceptibility.
    Full-text · Article · Jul 2014 · Journal of Neurodevelopmental Disorders
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