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From an early age, individuals with autism spectrum disorder (ASD) spend less time engaged in social interaction compared to typically developing peers (TD). One reason behind this behavior may be that the brains of children diagnosed with ASD do not attribute enough value to potential social exchanges as compared to the brains of typically developing children; thus, potential social exchanges are avoided because other environmental stimuli are more highly valued by default. Neurobiological investigations into the mechanisms underlying value-based decision-making has shown that the ventral medial prefrontal cortex (vmPFC) is critical for encoding the expected outcome value of different actions corresponding to distinct environmental cues. Here, we tested the hypothesis that the responsiveness of the vmPFC in children diagnosed with ASD (compared to TD controls) is diminished for visual cues that represent highly valued social interaction. Using a passive picture viewing task and functional magnetic resonance imaging (fMRI) we measured the response of an a priori defined region of interest in the vmPFC in children diagnosed with ASD and an age-matched TD cohort. We show that the average response of the vmPFC is significantly diminished in the ASD group. Further, we demonstrate that a single-stimulus and less than 30 s of fMRI data are sufficient to differentiate the ASD and TD cohorts. These findings are consistent with the hypothesis that the brains of children with ASD do not encode the value of social exchange in the same manner as TD children. The latter finding suggests the possibility of utilizing single-stimulus fMRI as a potential biologically based diagnostic tool to augment traditional clinical approaches. Wellcome Trust Principal Research Fellowship; Kane Family Foundation; Autism Speaks; Charles A. Dana Foundation; National Institutes of Health [RO1 DA11723, RO1 MH085496, T32 NS43124, UL1TR001420-KL2] This work was funded by a Wellcome Trust Principal Research Fellowship (PRM), Kane Family Foundation (PRM), Autism Speaks (PRM), the Charles A. Dana Foundation (PRM) and the National Institutes of Health (RO1 DA11723 (PRM), RO1 MH085496 (PRM), T32 NS43124 (KTK), UL1TR001420-KL2 (KTK)). The authors would like to thank the NEMO software development team for their assistance in programming the stimulus presentation scripts, and the Human Neuroimaging Laboratory's technological staff for their assistance with recruitment and scanning. more...

Increased public awareness of autism spectrum disorders (ASD) and routine screening in primary care have contributed to increased requests for diagnostic ASD evaluations. However, given the scarcity of subspecialty autism diagnostic resources, overreferral of children suspected of having ASD may be contributing to long waiting lists at tertiary care autism centers and delaying diagnosis for those children who truly have ASD. To determine whether children are being excessively referred to ASD-specific diagnostic clinics, our objective was to determine the prevalence of true ASD diagnoses in children referred for diagnostic ASD evaluation. Charts of all patients referred to a regional autism center between April 2011 and August 2012 for suspicion of a possible ASD were retrospectively reviewed and demographic and clinical diagnoses abstracted. Only 214 of 348 patients evaluated (61%) received an ASD diagnosis. Thus, concerns about autism are not confirmed by an ASD diagnosis in a significant number of children. more...

Mutations in Methyl-CpG-Binding protein 2 (MECP2) are commonly associated with and the neurodevelopmental disorder Rett syndrome (RTT). However, some people with RTT do not have mutations in MECP2, and interestingly there have been people identified with MECP2 mutations that do not have the clinical features of RTT. In this report we present four people with neurodevelopmental abnormalities and clear RTT-disease causing MECP2 mutation but lacking the characteristic clinical features of RTT. One patient's symptoms suggest an extension of the known spectrum of MECP2 associated phenotypes to include Global Developmental Delay (GDD) with Obsessive Compulsive Disorder (OCD) and Attention Deficit Hyperactivity Disorder (ADHD). These results furthermore reemphasize that RTT should remain a clinical diagnosis, based on the recent refurbished consensus criteria. more...

Purpose: Despite growing concerns toward maintaining participants' privacy, individual investigators collecting tissue and other biological specimens for genomic analysis are encouraged to obtain informed consent for broad data sharing. Our purpose was to assess the effect on research enrollment and data sharing decisions of three different consent types (traditional, binary, or tiered) with varying levels of control and choices regarding data sharing. Methods: A single-blinded, randomized controlled trial was conducted with 323 eligible adult participants being recruited into one of six genome studies at Baylor College of Medicine in Houston, Texas, between January 2008 and August 2009. Participants were randomly assigned to one of three experimental consent documents (traditional, n = 110; binary, n = 103; and tiered, n = 110). Debriefing in follow-up visits provided participants a detailed review of all consent types and the chance to change data sharing choices or decline genome study participation. Results: Before debriefing, 83.9% of participants chose public data release. After debriefing, 53.1% chose public data release, 33.1% chose restricted (controlled access database) release, and 13.7% opted out of data sharing. Only one participant declined genome study participation due to data sharing concerns. Conclusion: Our findings indicate that most participants are willing to publicly release their genomic data; however, a significant portion prefers restricted release. These results suggest discordance between existing data sharing policies and participants' judgments and desires. more...

Objective: To describe the cognitive and behavioral phenotypic features of the Potocki-Lupski syndrome (duplication 17p11.2), a recently recognized syndrome with multiple congenital anomalies and developmental delays. Method: Fifteen subjects were enrolled in an extensive multidisciplinary clinical protocol. Cognitive and behavior evaluations included a parent-report medical and psychological history form, intellectual assessment and assessments of adaptive behavior, executive functioning, and maladaptive behavior and emotions. Eight of the families completed an Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule-Generic. Results: The majority of patients (13 of 15) presented with intellectual disability. Moreover, the majority of patients also had moderate to severe behavioral difficulties, including atypicality, withdrawal, anxiety, and inattention. Many patients characterized also presented with autistic symptom pictures, some of whom (10 of 15) met diagnostic criteria for an autistic spectrum disorder, namely autistic disorder or pervasive developmental disorder not otherwise specified. Conclusion: This work expands on the behavioral phenotype of duplication 17p11.2 (Potocki-Lupski syndrome). Further phenotypic analysis will aid in clinical diagnosis, counseling, and management of this newly characterized microduplication syndrome. The association between this syndrome and autistic spectrum disorder may contribute to further understanding the etiology of the pervasive developmental disorders. more...

The duplication 17p11.2 syndrome, associated with dup(17)(p11.2p11.2), is a recently recognized syndrome of multiple congenital anomalies and mental retardation and is the first predicted reciprocal microduplication syndrome described--the homologous recombination reciprocal of the Smith-Magenis syndrome (SMS) microdeletion (del(17)(p11.2p11.2)). We previously described seven subjects with dup(17)(p11.2p11.2) and noted their relatively mild phenotype compared with that of individuals with SMS. Here, we molecularly analyzed 28 additional patients, using multiple independent assays, and also report the phenotypic characteristics obtained from extensive multidisciplinary clinical study of a subset of these patients. Whereas the majority of subjects (22 of 35) harbor the homologous recombination reciprocal product of the common SMS microdeletion (~3.7 Mb), 13 subjects (~37%) have nonrecurrent duplications ranging in size from 1.3 to 15.2 Mb. Molecular studies suggest potential mechanistic differences between nonrecurrent duplications and nonrecurrent genomic deletions. Clinical features observed in patients with the common dup(17)(p11.2p11.2) are distinct from those seen with SMS and include infantile hypotonia, failure to thrive, mental retardation, autistic features, sleep apnea, and structural cardiovascular anomalies. We narrow the critical region to a 1.3-Mb genomic interval that contains the dosage-sensitive RAI1 gene. Our results refine the critical region for Potocki-Lupski syndrome, provide information to assist in clinical diagnosis and management, and lend further support for the concept that genomic architecture incites genomic instability. more...

The unstable, gene-rich chromosome region 17p11.2-p12 is associated with various structural aberrations including supernumerary marker chromosomes (SMCs). In some cases, SMC(17)s utilize the same substrates for recombination as the common recurrent 17p11.2 and 17p12 rearrangements. We report on a 9-year-old girl with a de novo mosaic SMC(17). The der(17) encompasses genetic material from 17p10-p11.2 and is present in 97% of peripheral blood lymphocytes and in 79% of buccal cells. The patient has few features similar to individuals with duplication 17p11.2 including mental retardation, language impairment, and sleep disturbances but has normal growth, and no structural abnormalities of the heart, kidneys, or brain. She has no substantial behavioral abnormalities or dysmorphic features. Molecular analyses determined that the der(17) contains RAI1 but not PMP22. We found one chromosome breakpoint within the centromere and the second breakpoint within the distal Smith-Magenis syndrome low-copy repeat (distal SMS-REP). Recently we characterized the breakpoints of three other marker chromosomes originating from the proximal short arm of chromosome 17. In all four cases, one breakpoint maps within the centromere and in three cases the second breakpoint maps within a low-copy repeat. We thus propose that genome architecture may play a significant role in the formation of marker chromosomes. We present the cytogenetic, molecular, and clinical data of this patient and compare our results with those of patients with dup(17)(p11.2p11.2) syndrome and other patients with SMC(17). more...