AbstractBackgroundIndividuals with Autism Spectrum Disorders (ASD) typically show impaired eye contact during social interactions. From a young age, they look less at faces than typically developing (TD) children and tend to avoid direct gaze. However, the reason for this behavior remains controversial; ASD children might avoid eye contact because they perceive the eyes as aversive or because they do not find social engagement through mutual gaze rewarding.MethodsWe monitored pupillary diameter as a measure of autonomic response in children with ASD (n = 20, mean age = 12.4) and TD controls (n = 18, mean age = 13.7) while they looked at faces displaying different emotions. Each face displayed happy, fearful, angry or neutral emotions with the gaze either directed to or averted from the subjects.ResultsOverall, children with ASD and TD controls showed similar pupillary responses; however, they differed significantly in their sensitivity to gaze direction for happy faces. Specifically, pupillary diameter increased among TD children when viewing happy faces with direct gaze as compared to those with averted gaze, whereas children with ASD did not show such sensitivity to gaze direction. We found no group differences in fixation that could explain the differential pupillary responses. There was no effect of gaze direction on pupil diameter for negative affect or neutral faces among either the TD or ASD group.ConclusionsWe interpret the increased pupillary diameter to happy faces with direct gaze in TD children to reflect the intrinsic reward value of a smiling face looking directly at an individual. The lack of this effect in children with ASD is consistent with the hypothesis that individuals with ASD may have reduced sensitivity to the reward value of social stimuli.

Objective

To compare the relative long-term benefit of family-focused cognitive behavioral therapy (FCBT) and child-focused cognitive behavioral therapy (CCBT) for child anxiety disorders at a 1-year follow-up.

Method

Thirty-five children (6-13 years old) randomly assigned to 12-16 sessions of family-focused CBT (FCBT) or child-focused CBT (CCBT) participated in a 1-year follow-up assessment. Independent evaluators, parents, and children rated anxiety and parental intrusiveness. All were blind to treatment condition and study hypotheses.

Results

Children assigned to FCBT had lower anxiety scores than children assigned to CCBT on follow-up diagnostician- and parent-report scores, but not child-report scores. Exploratory analyses suggested the advantage of FCBT over CCBT may have been evident more for early adolescents than for younger children and that reductions in parental intrusiveness may have mediated the treatment effect.

Conclusion

FCBT may yield a stronger treatment effect than CCBT that lasts for at least 1 year, although the lack of consistency across informants necessitates a circumspect view of the findings. The potential moderating and mediating effects considered in this study offer interesting avenues for further study.

We compared the cognitive and language development at 4, 14, 24, 36, 54 months, and 7 years of siblings of children with autism (SIBS-A) to that of siblings of children with typical development (SIBS-TD) using growth curve analyses. At 7 years, 40% of the SIBS-A, compared to 16% of SIBS-TD, were identified with cognitive, language and/or academic difficulties, identified using direct tests and/or parental reports. This sub-group was identified as SIBS-A-broad phenotype (BP). Results indicated that early language scores (14–54 months), but not cognitive scores of SIBS-A-BP and SIBS-A-nonBP were significantly lower compared to the language scores of SIBS-TD, and that the rate of development was also significantly different, thus pinpointing language as a major area of difficulty for SIBS-A during the preschool years.

Abnormal eye contact is a core symptom of autism spectrum disorders (ASD), though little is understood of the neural bases of gaze processing in ASD. Competing hypotheses suggest that individuals with ASD avoid eye contact due to the anxiety-provoking nature of direct eye gaze or that eye-gaze cues hold less interest or significance to children with ASD. The current study examined the effects of gaze direction on neural processing of emotional faces in typically developing (TD) children and those with ASD. While undergoing functional magnetic resonance imaging (fMRI), 16 high-functioning children and adolescents with ASD and 16 TD controls viewed a series of faces depicting emotional expressions with either direct or averted gaze. Children in both groups showed significant activity in visual-processing regions for both direct and averted gaze trials. However, there was a significant group by gaze interaction such that only TD children showed reliably greater activity in ventrolateral prefrontal cortex for direct versus averted gaze. The ASD group showed no difference between direct and averted gaze in response to faces conveying negative emotions. These results highlight the key role of eye gaze in signaling communicative intent and suggest altered processing of the emotional significance of direct gaze in children with ASD.

We investigated whether deficits in social gaze and affect and in joint attention behaviors are evident within the first year of life among siblings of children with autism who go on to be diagnosed with autism or ASD (ASD) and siblings who are non-diagnosed (NoASD-sib) compared to low-risk controls. The ASD group did not differ from the other two groups at 6 months of age in the frequency of gaze, smiles, and vocalizations directed toward the caregiver, nor in their sensitivity to her withdrawal from interaction. However, by 12 months, infants in the ASD group exhibited lower rates of joint attention and requesting behaviors. In contrast, NoASD-sibs did not differ from comparison infants on any variables of interest at 6 and 12 months.

Child-mother attachment, as observed in the Strange Situation (SSP), was assessed in 61 families affected by HIV and 18 neighborhood comparison families not affected by HIV, but of similar ethnicity and socioeconomic status. Children were aged one to three years at the assessment. Secure attachment was significantly less likely among children in the HIV-affected group than among comparison group children (36% versus 67%). The most common pattern of attachment in the HIV-affected group was disorganized/disoriented, observed in 41% of children (versus 22% of comparison children). Children from families that included a surviving grandparent with HIV showed disorganized attachments more often than children whose grandparents died (53% versus 36%). Child attachment classifications were not associated with families' participation in a family-based, cognitive-behavioral HIV intervention. These results document the inter-generational impact of young mothers' who were growing up with an HIV-infected parent. These findings suggest that families affected by HIV may benefit from interventions that address attachment issues.

We observed infant siblings of children with autism later diagnosed with ASD (ASD siblings; n = 17), infant siblings of children with autism with and without other delays (Other Delays and No Delays siblings; n = 12 and n = 19, respectively) and typically developing controls (TD controls; n = 19) during a free-play task at 18 months of age. Functional, symbolic, and repeated play actions were coded. ASD siblings showed fewer functional and more non-functional repeated play behaviors than TD controls. Other Delays and No Delays siblings showed more non-functional repeated play than TD controls. Group differences disappeared with the inclusion of verbal mental age. Play as an early indicator of autism and its relationship to the broader autism phenotype is discussed.

Abstract Autism spectrum disorders have been associated with maternally derived duplications that involve the imprinted region on the proximal long arm of chromosome 15. Here we describe a boy with a chromosome 15 duplication arising from a 3:1 segregation error of a paternally derived translocation between chromosome 15q13.2 and chromosome 9q34.12, which led to trisomy of chromosome 15pter-q13.2 and 9q34.12-qter. Using array comparative genome hybridization, we localized the breakpoints on both chromosomes and sequence homology suggests that the translocation arose from non-allelic homologous recombination involving the low copy repeats on chromosome 15. The child manifests many characteristics of the maternally-derived duplication chromosome 15 phenotype including developmental delays with cognitive impairment, autism, hypotonia and facial dysmorphisms with nominal overlap of the most general symptoms found in duplications of chromosome 9q34. This case suggests that biallelically expressed genes on proximal 15q contribute to the idic(15) autism phenotype.

Background

Maternally-derived duplications that include the imprinted region on the proximal long arm of chromosome 15 underlie a complex neurobehavioral disorder characterized by cognitive impairment, seizures and a substantial risk for autism spectrum disorders1. The duplications most often take the form of a supernumerary pseudodicentric derivative chromosome 15 [der(15)] that has been called inverted duplication 15 or isodicentric 15 [idic(15)], although interstitial rearrangements also occur. Similar to the deletions found in most cases of Angelman and Prader Willi syndrome, the duplications appear to be mediated by unequal homologous recombination involving low copy repeats (LCR) that are found clustered in the region. Five recurrent breakpoints have been described in most cases of segmental aneuploidy of chromosome 15q11-q13 and previous studies have shown that most idic(15) chromosomes arise through BP3:BP3 or BP4:BP5 recombination events.

Results

Here we describe four duplication chromosomes that show evidence of atypical recombination events that involve regions outside the common breakpoints. Additionally, in one patient with a mosaic complex der(15), we examined homologous pairing of chromosome 15q11-q13 alleles by FISH in a region of frontal cortex, which identified mosaicism in this tissue and also demonstrated pairing of the signals from the der(15) and the normal homologues.

Conclusion

Involvement of atypical BP in the generation of idic(15) chromosomes can lead to considerable structural heterogeneity.

The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3x10(-39)), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.