The Genetics of Autistic Disorders and its Clinical Relevance: A Review of the Literature

Department of Child and Adolescent Psychiatry, Saarland University Hospital, Homburg, Germany.
Molecular Psychiatry (Impact Factor: 14.5). 02/2007; 12(1):2-22. DOI: 10.1038/
Source: PubMed


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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    • "The main goal of the current study was to examine whether the cognitive architecture underlying SPX and MPX autism families is different and useful for parsing etiological heterogeneity of ASD. This model of different etiologies in SPX and MPX families is based on evidence from behaviorally-based and genetic research (Sebat et al. 2007; Marshall et al. 2008; Freitag 2007; Virkud et al. 2009; Gerdts et al. 2013). We hypothesized that (a) the different forms of ASD might result in dissimilar cognitive profiles in SPX and MPX ASD probands, and (b) unaffected siblings from MPX but not SPX would display (mild) cognitive deficits compared to controls. "
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    ABSTRACT: Children with an autism spectrum disorder (ASD) and their unaffected siblings from 54 simplex (SPX, one individual in the family affected) and 59 multiplex (MPX, two or more individuals affected) families, and 124 controls were assessed on intelligence, social cognition and executive functions. SPX and MPX ASD probands displayed similar cognitive profiles, but within-family contrasts were highest in SPX families, suggesting SPX-MPX stratification may help parse etiological heterogeneity of ASD. Unaffected siblings (regardless SPX or MPX) were mostly unimpaired, suggesting that cognitive problems may be part of the defining features of ASD, rather than being an endophenotypic trait. Except for affective prosody, which appeared to be the most sensitive cognitive marker for detecting familial risk for ASD.
    Journal of Autism and Developmental Disorders 09/2015; DOI:10.1007/s10803-015-2572-9 · 3.06 Impact Factor
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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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