The Expanding Role of MBD Genes in Autism: Identification of a MECP2 Duplication and Novel Alterations in MBD5, MBD6, and SETDB1

Holly N. Cukier, Joycelyn M. Lee, Deqiong Ma, Juan I. Young, Vera Mayo, Brittany L. Butler, Sandhya S. Ramsook, Joseph A. Rantus, Alexander J. Abrams, Patrice L. Whitehead, Harry H. Wright, Ruth K. Abramson, Jonathan L. Haines, Michael L. Cuccaro, Margaret A. Pericak-Vance, and John R. Gilbert


The methyl-CpG-binding domain (MBD) family encompasses genes involved in the regulation of DNA chromatin structure. Alterations in two members of the MBD family, MBD5, and MECP2, have been identified in patients with a range of disorders including autism, learning disabilities, mental retardation, neonatal encephalopathy, repetitive behaviors, Rett syndrome, seizures, and speech impairments. Furthermore, there is evidence that these genes are expressed in the brain. These clinical and molecular findings hint that mutations in additional MBD genes may be related to autism and the broader autism spectrum disorder (ASD). In this study, we evaluated 287 patients with ASD and an equal number of controls for alterations in MECP2, MBD5, MBD6, SETDB1, and SETDB2. Single nucleotide changes were identified that were unique to ASD patients, predicted to be damaging and, in a few cases, present in multiple affected individuals within a family. We also identified a large duplication in MECP2 present in two brothers with developmental delay and intellectual disabilities. This is the first study to identify potentially pathogenic alterations in patients with ASD in MBD6 and SETDB1 and reinforces the role of MBD5 and MECP2 as genes involved in developmental disorders. © 2012 INSAR/Wiley Periodicals, Inc.

Article citation: Autism Res 2012, 5: 385–397. DOI: 10.1002/aur.1251

Delayed Reversal Learning and Association With Repetitive Behavior in Autism Spectrum Disorders

Mikle South, Tiffani Newton, and Paul D. Chamberlain


Autism spectrum disorders (ASDs) are associated with difficulties in being flexible as well as with significant anxiety. These symptoms often cause just as much distress as symptoms of social disability in autism for individuals, families, and communities. Difficulties with flexibility, especially to adapt to changing environmental situations, may link autism and anxiety together. We studied 30 children and adolescents diagnosed with ASD along with 29 controls with similar age and intelligence quotient. We adapted a task used to study flexibility in adults, beginning with two color cues. One color may be followed by a puff of air to the neck, which is not painful but is very surprising. The other color is always safe, with no air puff. Midway through the experiment the cues are reversed so what used to be safe is now threatening, and vice-versa. Compared with controls, the ASD group was delayed in their reversal of arousal to the new threat cue, and increased levels of repetitive behavior in everyday life were associated with decreased ability to make the reversal transition. Better characterization of the role of anxiety in ASD, including possible subtypes of anxiety and ASD, may improve understanding of both neurobiology and clinical presentation in autism and lead to better targeted treatments. © 2012 INSAR/Wiley Periodicals, Inc.

Article citation: Autism Res 2012, 5: 398–406. DOI: 10.1002/aur.1255

Deficits in Mental State Attributions in Individuals with 22q11.2 Deletion Syndrome (Velo-Cardio-Facial Syndrome)

Jennifer S. Ho1, Petya D. Radoeva1, Maria Jalbrzikowski, Carolyn Chow, Jessica Hopkins, Wen-Ching Tran, Ami Mehta, Nicole Enrique, Chelsea Gilbert, Kevin M. Antshel, Wanda Fremont, Wendy R. Kates1, and Carrie E. Bearden1


Velo-cardio-facial syndrome (VCFS) is caused by a genetic mutation associated with an increased risk of Autism Spectrum Disorder (ASD). One defining feature of ASD is the inability to understand others' thoughts and emotions (i.e. make mental state attributions), which may explain why persons with autism have such difficulty with reciprocal social interactions. The present study investigated the differences in mental state attribution between persons with VCFS as compared to typically developing controls. We conducted a study involving 63 individuals with VCFS and 43 typically developing controls using a task in which participants watched animated videos of two geometric shapes “interacting” with each other, in either Theory of Mind (ToM) interactions that elicit mental state attributions, or “Random” scenes in which no interaction takes place. We compared the accuracy and degree of mentalizing reported in participants' descriptions. Results indicated that persons with VCFS performed more poorly than controls in terms of both accuracy and mental state attributions when rating videos involving purposeful interaction; however, the groups did not differ for Random scenes. Individuals with VCFS, regardless of an ASD diagnosis, performed worse than controls in the mental state attribution task. Moreover, we found that real-world social problems were significantly related to performance on this task. This finding suggests that impairments in making mental state attributions could underlie social problems in persons with VCFS. © 2012 INSAR/Wiley Periodicals, Inc.

Article citation: Autism Res 2012, 5: 407–418. DOI: 10.1002/aur.1252

Molecular Characterisation of Gastrointestinal Microbiota of Children With Autism (With and Without Gastrointestinal Dysfunction) and Their Neurotypical Siblings

Shakuntla V. Gondalia, Enzo A. Palombo, Simon R. Knowles, Stephen B. Cox, Denny Meyer, and David W. Austin


Many children with autism spectrum disorders (ASD) suffer from gastrointestinal problems such as diarrhoea, constipation and abdominal pain. This has stimulated investigations into possible abnormalities of intestinal microflora in autistic patients. Therefore, we designed this study to identify differences (and/or similarities) in the microflora of children with autism (without gastrointestinal dysfunction: n = 23; with gastrointestinal dysfunction: n = 28) and their normally developing siblings (n = 53) who share a similar environment. Regardless of the diagnosis and sociodemographic characteristics, overall, Firmicutes (70%), Bacteroidetes (20%) and Proteobacteria (4%) were the most dominant bacterial phyla in samples. Results did not indicate clinically meaningful differences between groups. The data do not support the hypothesis that the gastrointestinal microflora of children with ASD plays a role in ASD. Other explanations for the gastrointestinal dysfunction in this population should be considered including elevated anxiety and self-restricted diets. © 2012 INSAR/Wiley Periodicals, Inc.

Article citation: Autism Res 2012, 5: 419–427. DOI: 10.1002/aur.1253

Amniotic Fluid MMP-9 and Neurotrophins in Autism Spectrum Disorders: An Exploratory Study

Morsi W. Abdallah, Brad D. Pearce, Nanna Larsen, Kirstin Greaves-Lord, Bent Nørgaard-Pedersen, David M. Hougaard, Erik L. Mortensen, and Jakob Grove


Brain plasticity refers to the ability of the brain to respond structurally and functionally to different environmental factors. Scientific evidence suggests that impairments in brain plasticity may play a role in the development of autism spectrum disorders (ASDs). In this study, different biologic markers closely related to brain plasticity were measured in samples of amniotic fluid from 331 children diagnosed later in life with ASD and 698 control children without ASD.

Amniotic fluid samples were retrieved from a large collection of amniotic fluid material kept and maintained at Statens Serum Institute in Copenhagen, Denmark. In addition, clinical and psychiatric data were retrieved from Danish national health registers.

Our results showed elevated levels of a biologic marker called matrix metalloproteinase (MMP)-9 that plays an important role in neurodevelopment. Our results of elevated levels of MMP-9 add to the evidence of potential role of impaired brain plasticity in ASD and may indicate that such impairments may be present during pregnancy. © 2012 INSAR/Wiley Periodicals, Inc.

Article citation: Autism Res 2012, 5: 428–433. DOI: 10.1002/aur.1254

Autism Risk Gene MET Variation and Cortical Thickness in Typically Developing Children and Adolescents

Alexis Hedrick, Yohan Lee, Gregory L. Wallace, Deanna Greenstein, Liv Clasen, Jay N. Giedd, and Armin Raznahan


Genetic factors and disruptions of cortical development are known to play a key role in the etiology of autism spectrum disorders (ASDs), but little is understood about how specific genetic variants might influence the development of cortical regions that have been implicated in ASD. One particular common variant in the gene MET receptor tyrosine kinase (MET), which is expressed in areas of the “social brain,” has been found to both impact gene function and occur more frequently in those with ASD compared with typically developing individuals. In animal studies, interfering with the function of this gene causes disruptions in the growth and migration of neurons during early development of the cortex. Therefore, we examined the relationship between this MET gene variant and cortical thickness in humans using repeated magnetic resonance imaging scans over the period of childhood and adolescence. We found that the presence of each additional risk allele was associated with a fixed decrease in cortical thickness in areas that are utilized for social interaction and that have frequently shown abnormalities in ASD. Our results suggest that genetic differences in the MET gene may influence the development of cortical systems implicated in the neurobiology of ASD. © 2012 INSAR/Wiley Periodicals, Inc.

Article citation: Autism Res 2012, 5: 434439. DOI: 10.1002/aur.1256

  1. 1

    Equal authorship contribution of the first two authors and the two senior authors.