Freitag, C. M. The genetics of autistic disorders and its clinical relevance: a review of the literature. Mol. Psychiatry 12, 2-22

Department of Child and Adolescent Psychiatry, Saarland University Hospital, Homburg, Germany.
Molecular Psychiatry (Impact Factor: 15.15). 02/2007; 12(1):2-22. DOI: 10.1038/
Source: PubMed

ABSTRACT Twin and family studies in autistic disorders (AD) have elucidated a high heritability of the narrow and broad phenotype of AD. In this review on the genetics of AD, we will initially delineate the phenotype of AD and discuss aspects of differential diagnosis, which are particularly relevant with regard to the genetics of autism. Cytogenetic and molecular genetic studies will be presented in detail, and the possibly involved aetiopathological pathways will be described. Implications of the different genetic findings for genetic counselling will be mentioned.

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Available from: Christine M. Freitag, Sep 24, 2014
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    • "In contrast, polygenic or multifactorial modes of inheritance (i.e. multiple (genetic) risk factors shared between family members) appear to play a more important role in MPX families (Freitag 2007), with studies showing that members of MPX families more often exhibit ASD traits compared to members of SPX families (Losh et al. 2008; Virkud et al. 2009; Schwichtenberg et al. 2010; Bernier et al. 2012). Thus, stratification according to family history seems sensitive in discriminating between (genetic) risk factors uniquely present in the proband (mostly present in SPX families) versus risk factors shared by multiple family members (in MPX families) (Sullivan et al. 2012). "
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    ABSTRACT: Autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) are highly heterogeneous neuropsychiatric disorders, that frequently co-occur. This study examined whether stratification into single-incidence (SPX) and multi-incidence (MPX) is helpful in (a) parsing heterogeneity and (b) detecting overlapping and unique underpinnings of the disorders. ASD and ADHD traits were measured in 56 ASD/31 ADHD SPX families, 59 ASD/171 ADHD MPX families and 203 control families. In ASD but not ADHD, behavioral traits were less elevated in SPX than MPX unaffected relatives, suggesting that SPX-MPX stratification may thus help parse ASD, but not ADHD heterogeneity. Particularly unaffected relatives from MPX ASD/ADHD families displayed elevated trait levels of both disorders, indicating shared (multifactorial) underpinnings underlying ASD and ADHD in these families. Cross-disorder traits were highest in MPX ASD unaffected siblings.
    Journal of Autism and Developmental Disorders 08/2014; 45(3). DOI:10.1007/s10803-014-2220-9 · 3.34 Impact Factor
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    • "ASD is a complex neurobehavioral disorder with a high degree of heritability [Freitag, 2007; Skuse, 2007]. Individual common variants identified by large-scale genomewide association studies appeared to exert weak effects on the risk for ASD, such that all variants together may explain only a modest part of the genetic component of the disease [Anney et al., 2012]. "
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    ABSTRACT: Although autism spectrum disorder (ASD) shows a high degree of heritability, only a few mutated genes and mostly de novo copy number variations (CNVs) with a high phenotypic impact have as yet been identified. In families with multiple ASD patients, transmitted CNVs often do not appear to cosegregate with disease. Therefore, also transmitted single nucleotide variants which escape detection if genetic analyses were limited to CNVs may contribute to disease risk. In several studies of ASD patients, CNVs covering at least one gene of the contactin gene family were found. To determine whether there is evidence for a contribution of transmitted variants in contactin genes, a cohort of 67 ASD patients and a population-based reference of 117 healthy individuals, who were not related to the ASD families, were compared. In total, 1,648 SNPs, spanning 12.1 Mb of genomic DNA, were examined. After Bonferroni correction for multiple testing, the strongest signal was found for a SNP located within the CNTN5 gene (rs6590473 [G], p = 4.09 × 10(-7); OR = 3.117; 95% CI = 1.603-6.151). In the ASD cohort, a combination of risk alleles of SNPs in CNTN6 (rs9878022 [A]; OR = 3.749) and in CNTNAP2 (rs7804520 [G]; OR = 2.437) was found more frequently than would be expected under random segregation, albeit this association was not statistically significant. The latter finding is consistent with a polygenic disease model in which multiple mutagenic mechanisms, operating concomitantly, elicit the ASD phenotype. Altogether, this study corroborates the possible involvement of contactins in ASD, which has been indicated by earlier studies of CNVs.
    Molecular syndromology 08/2014; 5(5):229-35. DOI:10.1159/000362891
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    • "There are indications that some de novo non-synonymous substitutions could be associated with various intellectual disabilities but the functional impact of these mutations is not well understood [45]. In general, ASD is a complex, multifactorial disorder [95-98] which makes construction of straightforward explanatory models highly problematic. Currently, we are still at the stage of searching for factors that are significantly and substantially associated with ASD. "
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    ABSTRACT: BackgroundA dramatic increase in the prevalence of autism and Autistic Spectrum Disorders (ASD) has been observed over the last two decades in USA, Europe and Asia. Given the accumulating data on the possible role of translation in the etiology of ASD, we analyzed potential effects of rare synonymous substitutions associated with ASD on mRNA stability, splicing enhancers and silencers, and codon usage.Presentation of the hypothesisWe hypothesize that subtle impairment of translation, resulting in dosage imbalance of neuron-specific proteins, contributes to the etiology of ASD synergistically with environmental neurotoxins.Testing the hypothesisA statistically significant shift from optimal to suboptimal codons caused by rare synonymous substitutions associated with ASD was detected whereas no effect on other analyzed characteristics of transcripts was identified. This result suggests that the impact of rare codons on the translation of genes involved in neuron development, even if slight in magnitude, could contribute to the pathogenesis of ASD in the presence of an aggressive chemical background. This hypothesis could be tested by further analysis of ASD-associated mutations, direct biochemical characterization of their effects, and assessment of in vivo effects on animal models.Implications of the hypothesisIt seems likely that the synergistic action of environmental hazards with genetic variations that in themselves have limited or no deleterious effects but are potentiated by the environmental factors is a general principle that underlies the alarming increase in the ASD prevalence.ReviewersThis article was reviewed by Andrey Rzhetsky, Neil R. Smalheiser, and Shamil R. Sunyaev.
    Biology Direct 07/2014; 9(1):16. DOI:10.1186/1745-6150-9-16 · 4.04 Impact Factor
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