1. Gau SS, Liao HM, Hong CC, Chien WH, Chen CH. {{Identification of two inherited copy number variants in a male with autism supports two-hit and compound heterozygosity models of Autism}}. {Am J Med Genet B Neuropsychiatr Genet};2012 (Jul 9)
Autism is a childhood-onset neurodevelopmental disorder with complex genetic mechanism underlying its etiology. Recent studies revealed that a few single de novo copy number variants of genomic DNA (copy number variants [CNVs]) are pathogenic and causal in some sporadic cases, adding support to the hypothesis that some sporadic autism might be caused by single rare mutation with large clinical effect. In this study, we report the detection of two novel private CNVs simultaneously in a male patient with autism. These two CNVs include a microduplication of approximately 4.5 Mb at chromosome 4q12-13.1 that was transmitted from his mother and a microdeletion of approximately 1.8 Mb at 5q32 that was transmitted from his father. Several genes such as LPHN3, POU4F3, SH3RF2, and TCERG1 mapped to these two regions have psychiatric implications. However, the parents had only mild degree of attention deficit symptoms but did not demonstrate any obvious autistic symptoms or psychopathology. Our findings indicate that each of these two CNVs alone may not be pathogenic enough to cause clinical symptoms in their respective carriers, and hence they can be transmitted within each individual family. However, concomitant presence of these two CNVs might result in the clinical phenotypes of the affected patient reported here. Thus, our report of this family may represent an example to show that two hits of CNV and the presence of compound heterozygosity might be important mechanisms underlying the pathogenesis of autism. (c) 2012 Wiley Periodicals, Inc.
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2. Greimel E, Nehrkorn B, Schulte-Ruther M, Fink GR, Nickl-Jockschat T, Herpertz-Dahlmann B, Konrad K, Eickhoff SB. {{Changes in grey matter development in autism spectrum disorder}}. {Brain Struct Funct};2012 (Jul 10)
Results on grey matter (GM) structural alterations in autism spectrum disorder (ASD) are inconclusive. Moreover, little is known about age effects on brain-structure abnormalities in ASD beyond childhood. Here, we aimed to examine regional GM volumes in a large sample of children, adolescents, and adults with ASD. Magnetic resonance imaging scans were obtained in 47 male ASD subjects and 51 matched healthy controls aged 8-50 years. We used whole-brain voxel-based morphometry to first assess group differences in regional GM volume across age. Moreover, taking a cross-sectional approach, group differences in age effects on regional GM volume were investigated. Compared to controls, ASD subjects showed reduced GM volumes in the anterior cingulate cortex, posterior superior temporal sulcus, and middle temporal gyrus. Investigation of group differences in age effects on regional GM volume revealed complex, region-specific alterations in ASD. While GM volumes in the amygdala, temporoparietal junction, septal nucleus and middle cingulate cortex increased in a negative quadratic fashion in both groups, data indicated that GM volume curves in ASD subjects were shifted to the left along the age axis. Moreover, while GM volume in the right precentral gyrus decreased linearly with age in ASD individuals, GM volume development in controls followed a U-shaped pattern. Based on a large sample, our voxel-based morphometry results on group differences in regional GM volumes help to resolve inconclusive findings from previous studies in ASD. Results on age-related changes of regional GM volumes suggest that ASD is characterized by complex alterations in lifetime trajectories of several brain regions that underpin social-cognitive and motor functions.
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3. Grether JK, Qian Y, Croughan MS, Wu YW, Schembri M, Camarano L, Croen LA. {{Is Infertility Associated with Childhood Autism?}}. {J Autism Dev Disord};2012 (Jul 10)
Concerns persist about a possible link between infertility and risk of autism spectrum disorders (ASD). Interpretation of existing studies is limited by racial/ethnic homogeneity of study populations and other factors. Using a case-control design, we evaluated infertility history and treatment documented in medical records of members of Kaiser Permanente Northern California. Among singletons (349 cases, 1,847 controls), we found no evidence to support an increase in risk of ASD associated with infertility. Among multiple births (21 cases, 54 controls), we found an increased risk associated with infertility history and with infertility evaluations and treatment around the time of index pregnancy conception; however, small sample size and lack of detailed data on treatments preclude firm interpretation of results for multiple births.
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4. Guo T, Chen H, Liu B, Ji W, Yang C. {{Methylenetetrahydrofolate Reductase Polymorphisms C677T and Risk of Autism in the Chinese Han Population}}. {Genet Test Mol Biomarkers};2012 (Jul 9)
Causes of autism are still unknown. Some studies have shown that autism might be associated with metabolic abnormalities in the folate/homocysteine pathway, which is involved in DNA methylation, thus altering gene expression. The association between the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphisms and the risk of autism is still controversial and ambiguous. The purpose of this study was to examine the effect of the MTHFR C677T polymorphism on the autism risk in the Chinese Han population. A population-based case-control study was conducted in 186 children with autism and 186 controls. The MTHFR C677T polymorphisms were determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. The frequency of genotype MTHFR 677TT in children with autism (16.1%) was significantly higher (odds ratio [OR]=2.04; 95% confidence interval [CI]=1.07, 3.89; p=0.03] than those in controls (8.6%). When stratifying by select-item scores on the Autism Diagnostic Interview-Revised, it was found that children with current overactivity had a significantly higher frequency of the MTHFR 677TT genotype (OR=2.77, 95% CI=1.17, 6.60; p=0.02) than those without. This study suggested that MTHFR C677T is a risk factor of autism in Chinese Han children.
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5. Kelley K, Chang SJ, Lin SL. {{Mechanism of Repeat-Associated MicroRNAs in Fragile X Syndrome}}. {Neural Plast};2012;2012:104796.
The majority of the human genome is comprised of non-coding DNA, which frequently contains redundant microsatellite-like trinucleotide repeats. Many of these trinucleotide repeats are involved in triplet repeat expansion diseases (TREDs) such as fragile X syndrome (FXS). After transcription, the trinucleotide repeats can fold into RNA hairpins and are further processed by Dicer endoribonuclases to form microRNA (miRNA)-like molecules that are capable of triggering targeted gene-silencing effects in the TREDs. However, the function of these repeat-associated miRNAs (ramRNAs) is unclear. To solve this question, we identified the first native ramRNA in FXS and successfully developed a transgenic zebrafish model for studying its function. Our studies showed that ramRNA-induced DNA methylation of the FMR1 5′-UTR CGG trinucleotide repeat expansion is responsible for both pathological and neurocognitive characteristics linked to the transcriptional FMR1 gene inactivation and the deficiency of its protein product FMRP. FMRP deficiency often causes synapse deformity in the neurons essential for cognition and memory activities, while FMR1 inactivation augments metabotropic glutamate receptor (mGluR)-activated long-term depression (LTD), leading to abnormal neuronal responses in FXS. Using this novel animal model, we may further dissect the etiological mechanisms of TREDs, with the hope of providing insights into new means for therapeutic intervention.
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6. van Steensel FJ, Bogels SM, Dirksen CD. {{Anxiety and Quality of Life: Clinically Anxious Children With and Without Autism Spectrum Disorders Compared}}. {J Clin Child Adolesc Psychol};2012 (Jul 9)
Comorbid anxiety disorders are common in children with autism spectrum disorders (ASD). However, studies comparing children with ASD to clinically anxious children are rare. This study investigated anxiety problems and health-related quality of life in children with high-functioning ASD and comorbid anxiety disorders (referred to as the ASD group), compared with children with anxiety disorders (referred to as the AD group). In total, 237 families participated; 115 children were in the ASD group (90 boys and 25 girls, M age = 11.37 years), and 122 children were in the AD group (62 boys and 60 girls, M age = 12.79 years). Anxiety disorders, anxiety symptoms, ASD-like symptoms, and health-related quality of life were assessed with the ADIS-C/P, SCARED-71, CSBQ, and EuroQol-5D, respectively. The number and types of anxiety disorders, as well as their severity, were similar in the ASD and AD groups; however, specific phobias were more common in the ASD group than in the AD group. As compared to the AD group, parents from the ASD group reported their children to have higher scores for total anxiety, social anxiety disorder, and panic disorder. More ASD-like behaviors and higher anxiety severity predicted a lower quality of life, irrespective of group. The results of this study support a highly similar phenotype of anxiety disorders in children with ASD; however, additional research is needed to examine the etiology and treatment effectiveness of anxiety disorders in children with ASD.
