1. Chaste P, Sanders SJ, Mohan KN, Klei L, Song Y, Murtha MT, Hus V, Lowe JK, Willsey AJ, Moreno-De-Luca D, Yu TW, Fombonne E, Geschwind D, Grice DE, Ledbetter DH, Lord C, Mane SM, Martin DM, Morrow EM, Walsh CA, Sutcliffe JS, State MW, Martin CL, Devlin B, Beaudet AL, Cook EH, Jr., Kim SJ. {{Modest Impact on Risk for Autism Spectrum Disorder of Rare Copy Number Variants at 15q11.2, Specifically Breakpoints 1 to 2}}. {Autism Res};2014 (May 12)
The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1-BP2 CNVs and autism accumulates, the magnitude of the effect of BP1-BP2 CNVs remains elusive, posing a great challenge to recurrence-risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1-BP2 CNVs for ASD as well as their effects on ASD-related phenotypes in a well-characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1-BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD-related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1-BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status. Autism Res 2014, : -. (c) 2014 International Society for Autism Research, Wiley Periodicals, Inc.
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2. Sungur AO, Vorckel KJ, Schwarting RK, Wohr M. {{Repetitive Behaviors in the Shank1 Knockout Mouse Model for Autism Spectrum Disorder: Developmental Aspects and Effects of Social Context}}. {J Neurosci Methods};2014 (May 9)
BACKGROUND: Autism spectrum disorder (ASD) is characterized by persistent deficits in social behavior and communication, together with restricted and repetitive patterns of behavior. Several ASD candidate genes have been identified, including the SHANK gene family with its three family members SHANK1, SHANK2, and SHANK3. METHODS: Typically, repetitive behavior in mouse models for ASD is assessed by measuring self-grooming behavior. The first aim of the current study was to assess repetitive behaviors in Shank1-/- null mutant, Shank1+/- heterozygous, and Shank1+/+ wildtype littermate control mice by means of a comprehensive approach, including the assessment of self-grooming, digging behavior, and marble burying. The second aim was to establish a test paradigm that allows for assessing the effects of social context on the occurrence of repetitive behaviors in a genotype-dependent manner. To this aim, repetitive behaviors were repeatedly tested on three consecutive days in distinct social contexts, namely in presence or absence of social odors. RESULTS: Shank1+/- heterozygous and to a lesser extent Shank1-/- null mutant mice displayed slightly elevated levels of self-grooming behavior as adults, but not as juveniles, with genotype differences being most prominent in the social context. In contrast to elevated self-grooming behavior, marble burying was strongly reduced in adult Shank1+/- heterozygous and Shank1-/- null mutant mice across social contexts, as compared to adult Shank1+/+ wildtype littermate controls. CONCLUSION: The opposite effects of the Shank1 deletion on the two types of repetitive behaviors are in line with a number of studies on repetitive behaviors in other genetic Shank models.
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3. van der Meer JM, Lappenschaar MG, Hartman CA, Greven CU, Buitelaar JK, Rommelse NN. {{Homogeneous Combinations of ASD-ADHD Traits and Their Cognitive and Behavioral Correlates in a Population-Based Sample}}. {J Atten Disord};2014 (May 12)
Objective: Autism Spectrum Disorders (ASD) and ADHD are assumed to be the extreme manifestations of continuous heterogeneous traits that frequently co-occur. This study aims to identify subgroups of children with distinct ASD-ADHD trait profiles in the general population, using measures sensitive across both trait continua, and show how these subgroups differ in cognitive functioning. Method: We examined 378 children (6-13 years) from a population-based sample. Results: Latent class analyses (LCA) detected three concordant classes with low (10.1%), medium (54.2%), or high (13.2%) scores on both traits, and two discordant classes with more ADHD than ASD characteristics (ADHD > ASD, 18.3%) and vice versa (ASD > ADHD, 4.2%). Findings suggest that ASD and ADHD traits usually are strongly related in the unaffected population, and that a minority of children displays atypical discordant trait profiles characterized by differential visual-spatial functioning. Conclusion: This dissociation suggests that heterogeneity in ASD and ADHD is rooted in heterogeneity in the lower unaffected end of the distribution.
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4. Waddington H, Sigafoos J, Lancioni GE, O’Reilly MF, van der Meer L, Carnett A, Stevens M, Roche L, Hodis F, Green VA, Sutherland D, Lang R, Marschik PB. {{Three children with autism spectrum disorder learn to perform a three-step communication sequence using an iPad(R)-based speech-generating device}}. {Int J Dev Neurosci};2014 (May 9)
BACKGROUND: Many children with autism spectrum disorder (ASD) have limited or absent speech and might therefore benefit from learning to use a speech-generating device (SGD). The purpose of this study was to evaluate a procedure aimed at teaching three children with ASD to use an iPad(R)-based SGD to make a general request for access to toys, then make a specific request for one of two toys, and then communicate a thank-you response after receiving the requested toy. METHOD: A multiple-baseline across participants design was used to determine whether systematic instruction involving least-to-most-prompting, time delay, error correction, and reinforcement was effective in teaching the three children to engage in this requesting and social communication sequence. Generalization and follow-up probes were conducted for two of the three participants. RESULTS: With intervention, all three children showed improvement in performing the communication sequence. This improvement was maintained with an unfamiliar communication partner and during the follow-up sessions. CONCLUSION: With systematic instruction, children with ASD and severe communication impairment can learn to use an iPad-based SGD to complete multi-step communication sequences that involve requesting and social communication functions.
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5. Waltes R, Gfesser J, Haslinger D, Schneider-Momm K, Biscaldi M, Voran A, Freitag CM, Chiocchetti AG. {{Common EIF4E variants modulate risk for autism spectrum disorders in the high-functioning range}}. {J Neural Transm};2014 (May 13)
The genetic architecture of Autism Spectrum Disorders (ASD) is complex. Common genetic variation has especially been related to high-functioning ASD. In addition, some studies favoured analysis of strictly diagnosed autism individuals, which resulted in more robust findings than the combined analysis of all spectrum individuals. Functional variants modulating EIF4E expression have previously been indicated as risk factors for ASD. Pharmacological modulation of glutamate receptors which regulate EIF4E activity resulted in reduced repetitive behaviours in human and animal studies. Based on these findings, we tested common EIF4E variants for association with overall ASD, with strict autism and with the strict high-functioning autism (strict HFA) subgroup, and their effect on repetitive and/or stereotypic behaviour. We observed over-transmission of rs13109000G in the strict HFA and the strict autism cohort but not in the larger ASD cohort. We report protective effects for the minor allele of rs4699369T on stereotyped and ritualized behaviour in the overall ASD cohort, the strict autism but not in the strict HFA group. In addition, a protective role for rs4699369T and a risk effect of rs12498533G on hand and finger mannerisms was observed. These results need to be replicated in larger ASD and strict autism samples. The predicted impact on transcription through the ASD associated EIF4E variants rs4699369T and rs12498533G as well as the association of the EIF4E interaction partners FMRP and CYFIP1 with ASD point to an mRNA mediated pathomechanism for ASD.
