The genetics of autism spectrum disorders - a guide for clinicians.

Faculty of Medicine, University of Heidelberg, Im Neuenheimer Feld 134b, 69120, Heidelberg, Germany, .
Current Psychiatry Reports (Impact Factor: 3.05). 01/2013; 15(1):334. DOI: 10.1007/s11920-012-0334-3
Source: PubMed

ABSTRACT Recent advances in genetic testing technology have made chromosome microarray analysis (CMA) a first-tier clinical diagnostic test for Autism Spectrum Disorders (ASDs). Two main types of microarrays are available, single nucleotide polymorphism (SNP) arrays and array comparative genomic hybridization (aCGH), each with its own advantages and disadvantages in ASDs testing. Rare genetic variants, and copy number variants (CNVs) in particular, have been shown to play a major role in ASDs. More than 200 autism susceptibility genes have been identified to date, and complex patterns of inheritance, such as oligogenic heterozygosity, appear to contribute to the etiopathogenesis of ASDs. Incomplete penetrance and variable expressivity represent particular challenges in the interpretation of CMA testing of autistic individuals. This review aims to provide an overview of autism genetics for the practicing physician and gives hands-on advice on how to follow-up on abnormal CMA findings in individuals with neuropsychiatric disorders.

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    ABSTRACT: We report on two patients with intragenic deletions of RBFOX1 and one patient with an intragenic duplication of RBFOX1. These patients, by report, all had autism spectrum disorder and/or developmental delay and had strong family histories of these conditions. We initially hypothesized that RBFOX1 was another susceptibility locus for autism spectrum disorder or developmental delay. However, epidemiological evidence examining large numbers of individuals did not support this hypothesis and the data presented here suggests that RBFOX1 intragenic copy number variants are not pathogenic. This contradicts previous reports that examined smaller numbers of patients and controls. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 06/2014; 164(6). DOI:10.1002/ajmg.a.36458 · 2.05 Impact Factor
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    ABSTRACT: Copy number variations (CNVs) are an important cause of ASD and those located at 15q11-q13, 16p11.2 and 22q13 have been reported as the most frequent. These CNVs exhibit variable clinical expressivity and those at 15q11-q13 and 16p11.2 also show incomplete penetrance. In the present work, through multiplex ligation-dependent probe amplification (MLPA) analysis of 531 ethnically admixed ASD-affected Brazilian individuals, we found that the combined prevalence of the 15q11-q13, 16p11.2 and 22q13 CNVs is 2.1% (11/531). Parental origin could be determined in 8 of the affected individuals, and revealed that 4 of the CNVs represent de novo events. Based on CNV prediction analysis from genome-wide SNP arrays, the size of those CNVs ranged from 206 kb to 2.27 Mb and those at 15q11-q13 were limited to the 15q13.3 region. In addition, this analysis also revealed 6 additional CNVs in 5 out of 11 affected individuals. Finally, we observed that the combined prevalence of CNVs at 15q13.3 and 22q13 in ASD-affected individuals with epilepsy (6.4%) was higher than that in ASD-affected individuals without epilepsy (1.3%; p<0.014). Therefore, our data show that the prevalence of CNVs at 15q13.3, 16p11.2 and 22q13 in Brazilian ASD-affected individuals is comparable to that estimated for ASD-affected individuals of pure or predominant European ancestry. Also, it suggests that the likelihood of a greater number of positive MLPA results might be found for the 15q13.3 and 22q13 regions by prioritizing ASD-affected individuals with epilepsy.
    PLoS ONE 09/2014; 9(9):e107705. DOI:10.1371/journal.pone.0107705 · 3.53 Impact Factor
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    ABSTRACT: Abstract Objective: Little is known about the effectiveness of pharmacological interventions on autism spectrum disorder (ASD). This is a systematic review of the randomized controlled trials (RCTs) of oxytocin interventions in autism, made from January 1990 to September 2013. Method: A search of computerized databases was supplemented by manual search in the bibliographies of key publications. The methodological quality of the studies included in the review was evaluated independently by two researchers, according to a set of formal criteria. Discrepancies in scoring were resolved through discussion. Results: The review yielded seven RCTs, including 101 subjects with ASD (males=95) and 8 males with Fragile X syndrome. The main categories of target symptoms tested in the studies were repetitive behaviors, eye gaze, and emotion recognition. The studies had a medium to high risk of bias. Most studies had small samples (median=15). All the studies but one reported statistically significant between-group differences on at least one outcome variable. Most findings were characterized by medium effect size. Only one study had evidence that the improvement in emotion recognition was maintained after 6 weeks of treatment with intranasal oxytocin. Overall, oxytocin was well tolerated and side effects, when present, were generally rated as mild; however, restlessness, increased irritability, and increased energy occurred more often under oxytocin. Conclusions: RCTs of oxytocin interventions in autism yielded potentially promising findings in measures of emotion recognition and eye gaze, which are impaired early in the course of the ASD condition and might disrupt social skills learning in developing children. There is a need for larger, more methodologically rigorous RCTs in this area. Future studies should be better powered to estimate outcomes with medium to low effect size, and should try to enroll female participants, who were rarely considered in previous studies. Risk of bias should be minimized. Human long-term administration studies are necessary before clinical recommendations can be made.
    Journal of child and adolescent psychopharmacology 03/2014; 24(2):54-68. DOI:10.1089/cap.2013.0040 · 3.07 Impact Factor


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Jun 3, 2014