Transmission Disequilibrium of Small CNVs in Simplex Autism

Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 09/2013; 93(4). DOI: 10.1016/j.ajhg.2013.07.024
Source: PubMed


We searched for disruptive, genic rare copy-number variants (CNVs) among 411 families affected by sporadic autism spectrum disorder (ASD) from the Simons Simplex Collection by using available exome sequence data and CoNIFER (Copy Number Inference from Exome Reads). Compared to high-density SNP microarrays, our approach yielded ∼2× more smaller genic rare CNVs. We found that affected probands inherited more CNVs than did their siblings (453 versus 394, p = 0.004; odds ratio [OR] = 1.19) and that the probands' CNVs affected more genes (921 versus 726, p = 0.02; OR = 1.30). These smaller CNVs (median size 18 kb) were transmitted preferentially from the mother (136 maternal versus 100 paternal, p = 0.02), although this bias occurred irrespective of affected status. The excess burden of inherited CNVs among probands was driven primarily by sibling pairs with discordant social-behavior phenotypes (p < 0.0002, measured by Social Responsiveness Scale [SRS] score), which contrasts with families where the phenotypes were more closely matched or less extreme (p > 0.5). Finally, we found enrichment of brain-expressed genes unique to probands, especially in the SRS-discordant group (p = 0.0035). In a combined model, our inherited CNVs, de novo CNVs, and de novo single-nucleotide variants all independently contributed to the risk of autism (p < 0.05). Taken together, these results suggest that small transmitted rare CNVs play a role in the etiology of simplex autism. Importantly, the small size of these variants aids in the identification of specific genes as additional risk factors associated with ASD.

    • "Second, it suggests that the unaffected siblings from SPX families are not completely free from cognitive deficits. The finding is consistent with findings that although de novo genetic variations most likely play a role in the development of simplex ASD, they do not fully explain genetic etiology (Krumm et al. 2013). In other words, also in SPX ASD families some risks may be shared between family members (Klei et al. 2012), and the distinction between MPX and SPX ASD may reflect variation in the magnitude of effects rather than qualitative differences between groups. "
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    ABSTRACT: Children with an autism spectrum disorder (ASD) and their unaffected siblings from 54 simplex (SPX, one individual in the family affected) and 59 multiplex (MPX, two or more individuals affected) families, and 124 controls were assessed on intelligence, social cognition and executive functions. SPX and MPX ASD probands displayed similar cognitive profiles, but within-family contrasts were highest in SPX families, suggesting SPX-MPX stratification may help parse etiological heterogeneity of ASD. Unaffected siblings (regardless SPX or MPX) were mostly unimpaired, suggesting that cognitive problems may be part of the defining features of ASD, rather than being an endophenotypic trait. Except for affective prosody, which appeared to be the most sensitive cognitive marker for detecting familial risk for ASD.
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    • "Thus, whilst factors uniquely present in the affected child (such as de novo mutations) might underlie ASD in some of the SPX cases, multifactorial risk factors might still underlie the disorder in others. This is supported by genetic findings that de novo variations most likely play a role in the development of simplex ASD, but do not fully explain genetic etiology (Krumm et al. 2013). "
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    ABSTRACT: Autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) are highly heterogeneous neuropsychiatric disorders, that frequently co-occur. This study examined whether stratification into single-incidence (SPX) and multi-incidence (MPX) is helpful in (a) parsing heterogeneity and (b) detecting overlapping and unique underpinnings of the disorders. ASD and ADHD traits were measured in 56 ASD/31 ADHD SPX families, 59 ASD/171 ADHD MPX families and 203 control families. In ASD but not ADHD, behavioral traits were less elevated in SPX than MPX unaffected relatives, suggesting that SPX-MPX stratification may thus help parse ASD, but not ADHD heterogeneity. Particularly unaffected relatives from MPX ASD/ADHD families displayed elevated trait levels of both disorders, indicating shared (multifactorial) underpinnings underlying ASD and ADHD in these families. Cross-disorder traits were highest in MPX ASD unaffected siblings.
    Full-text · Article · Aug 2014 · Journal of Autism and Developmental Disorders
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    • "Int. (2013), et al., 2013), including copy number variants (CNVs) (Griswold et al., 2012; Holt et al., 2012; Krumm et al., 2013; Menashe et al., 2013; Poultney et al., 2013; Vaishnavi et al., 2013) as well as single nucleotide polymorphisms (SNPs). Because de novo coding mutations are low in probability, particularly in the coding regions of genes, geneticists consider de novo variations to be of particular significance in establishing genetic risk. "
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    ABSTRACT: Alterations in dopamine (DA) signaling underlie the most widely held theories of molecular and circuit level perturbations that lead to risk for attention-deficit hyperactivity disorder (ADHD). The DA transporter (DAT), a presynaptic reuptake protein whose activity provides critical support for DA signaling by limiting DA action at pre- and postsynaptic receptors, has been consistently associated with ADHD through pharmacological, behavioral, brain imaging and genetic studies. Currently, the animal models of ADHD exhibit significant limitations, stemming in large part from their lack of construct validity. To remedy this situation, we have pursued an effort to create a mouse model derived from functional nonsynonymous variation in the DAT gene (SLC6A3) of ADHD probands. We trace our path from the identification of these variants to in vitro biochemical and physiological studies to the production of the DAT Val559 mouse model. We discuss our initial findings with these animals and their promise in the context of existing rodent models of ADHD.
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