Genetics of autistic disorders: Review and clinical implications

Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Johann Wolfgang Goethe-University, Deutschordenstrasse 50, Frankfurt am Main, Germany.
European Child & Adolescent Psychiatry (Impact Factor: 3.34). 11/2009; 19(3):169-78. DOI: 10.1007/s00787-009-0076-x
Source: PubMed


Twin and family studies in autistic disorders (AD) have elucidated a high heritability of AD. In this literature review, we will present an overview on molecular genetic studies in AD and highlight the most recent findings of an increased rate of copy number variations in AD. An extensive literature search in the PubMed database was performed to obtain English published articles on genetic findings in autism. Results of linkage, (genome wide) association and cytogenetic studies are presented, and putative aetiopathological pathways are discussed. Implications of the different genetic findings for genetic counselling and genetic testing at present will be described. The article ends with a prospectus on future directions.

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Available from: Christine M. Freitag, Sep 24, 2014
    • "According to multiple family and twin studies reporting a substantial heritable component ranging between 70 and 90 % of autism etiology (Bailey et al. 1995; Freitag 2011; Folstein and Rosen-Sheidley 2001), ASD is considered to be one of the most strongly genetically influenced multifactorial childhood psychiatric disorders (Hallmayer et al. 2011). Despite the high heritability, the genetics are inferred to be complex and no major gene has been identified to be relevant for the majority of ASD diagnoses (Freitag et al. 2010). In the past decades, various studies have implicated a small amount of genes with either rare highly penetrant mutations, lowpenetrant common variants or copy-number variants (CNV) that together explain only about 15–30 % of the population prevalence (Sampath et al. 2013; Anney et al. 2010; Klei et al. 2012). "
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    ABSTRACT: The Contactin Associated Protein-like 2 (CNTNAP2) gene has been discussed to be associated with different symptoms of autism spectrum disorders (ASDs) and other neurodevelopmental disorders. We aimed to elucidate the genetic association of CNTNAP2 within high functioning ASD (HFA), focusing on autism specific symptoms and reducing intelligence related factors. Furthermore, we compared our findings conducting a meta-analysis in patients with ASD and HFA only. A case-control association study was performed for HFA (HFA, n = 105; controls, n = 133). Moreover, we performed a family-based association study (DFAM) analysis (HFA, n = 44; siblings, n = 57). Individuals were genotyped for the two most frequently reported single nucleotide polymorphisms (SNPs) in the CNTNAP2 gene (rs2710102, rs7794745). Furthermore, a meta-analysis using the MIX2 software integrated our results with previously published data. A significant association for the carriers of the T-allele of the rs7794745 with HFA was found in the case-control sample [OR = 1.547; (95 % CI 1.056-2.266); p = 0.025]. No association could be found by DFAM with any of the CNTNAP2 SNPs with HFA. The meta-analysis of both SNPs did not show a significant association with either ASD or with HFA. Overall, including case-control, sibs, and meta-analysis, we could not detect any significant association with the CNTNAP2 gene and HFA. Our results point in the direction that CNTNAP2 may not play a major role in HFA, but rather seems to have a significance in neurodevelopmental disorders or in individuals displaying intellectual delays.
    Journal of Neural Transmission 11/2015; DOI:10.1007/s00702-015-1458-5 · 2.40 Impact Factor
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    • "Although there is strong evidence for genetic factors in ASD, it appears to be a polygenic condition (Betancur 2011), and also responsive to a range of environmental events. Although, its precise etiology is unknown , ASD is clearly a complex human genetic disorder that involves interactions between genes and environment (Freitag et al. 2010; Li et al. 2014). Future integrative epigenomic analyses of genetic risk factors for environmental exposures and methylome analyses are expected to be important for understanding the complex etiology of ASD (LaSalle 2014). "
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    ABSTRACT: Autism research continues to receive considerable attention as the options for successful management are limited. The understanding of the autism spectrum disorder (ASD) etiology has now progressed to encompass genetic, epigenetic, neurological, hormonal, and environmental factors that affect outcomes for patients with ASD. Glycosaminoglycans (GAGs) are a family of linear, sulfated polysaccharides that are associated with central nervous system (CNS) development, maintenance, and disorders. Proteoglycans (PG) regulate diverse functions in the central nervous system. Heparan sulfate (HS) and chondroitin sulfate (CS) are two major GAGs present in the PGs of the CNS. As neuroscience advances, biochemical treatments to correct brain chemistry become better defined. Nutrient therapy can be very potent and has minimal to no side effects, since no molecules foreign to the body are needed. Given GAGs are involved in several neurological functions, and that its level can be somewhat modulated by the diet, the present study aimed to evaluate the role of GAGs levels in ASD symptoms. Both tGAG and its different fractions were evaluated in the urine of ASD and healthy control childrens. As levels differed between groups, a second trial was conduted evaluating if diet could reduce tGAG levels and if this in turn decrease ASD symptoms. The present study found that tGAG concentration was significantly higher in the urine of children with ASD compared to healthy control children and this was also evident in all GAG fractions. Within groups (controls and ASD), no gender differences in GAG excretion were found. The use of a 90 days elimination diet (casein-free, special carbohydrates, multivitamin/mineral supplement), had major effects in reducing urinary tGAG excretion in children with ASD.
    Metabolic Brain Disease 10/2015; DOI:10.1007/s11011-015-9745-2 · 2.64 Impact Factor
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    • "Family and twin studies strongly support a genetic predisposition for autism spectrum disorders (ASD), a neurodevelopmental disorder characterized by deficits in social interaction, communication, and repetitive behaviour [1,2]. However, no genes capable of explaining the majority of cases have been identified to date. "
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    ABSTRACT: Validating the potential pathogenicity of copy number variants (CNVs) identified in genome-wide studies of autism spectrum disorders (ASD) requires detailed assessment of case/control frequencies, inheritance patterns, clinical correlations, and functional impact. Here, we characterize a small recurrent duplication in the annexin A1 (ANXA1) gene, identified by the Autism Genome Project (AGP) study. From the AGP CNV genomic screen in 2,147 ASD individuals, we selected for characterization an ANXA1 gene duplication that was absent in 4,964 population-based controls. We further screened the duplication in a follow-up sample including 1,496 patients and 410 controls, and evaluated clinical correlations and family segregation. Sequencing of exonic/downstream ANXA1 regions was performed in 490 ASD patients for identification of additional variants. The ANXA1 duplication, overlapping the last four exons and 3'UTR region, had an overall prevalence of 11/3,643 (0.30%) in unrelated ASD patients but was not identified in 5,374 controls. Duplication carriers presented no distinctive clinical phenotype. Family analysis showed neuropsychiatric deficits and ASD traits in multiple relatives carrying the duplication, suggestive of a complex genetic inheritance. Sequencing of exonic regions and the 3'UTR identified 11 novel changes, but no obvious variants with clinical significance. We provide multilevel evidence for a role of ANXA1 in ASD etiology. Given its important role as mediator of glucocorticoid function in a wide variety of brain processes, including neuroprotection, apoptosis, and control of the neuroendocrine system, the results add ANXA1 to the growing list of rare candidate genetic etiological factors for ASD.
    Molecular Autism 04/2014; 5(1):28. DOI:10.1186/2040-2392-5-28 · 5.41 Impact Factor
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