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: 3.55). 11/2009; 19(3):169-78. DOI: 10.1007/s00787-009-0076-x
Source: PubMed

ABSTRACT 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
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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 · 5.49 Impact Factor
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    • "respectively. Given that ASD itself is a highly heritable disorder [8] with subclinical autistic traits found in parents [9], it is surprising that the presence of these problems has not been studied in parents of children with ASD. "
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    ABSTRACT: Atypical reactions to sensory stimuli show heritability in the general population and are a known risk factor for affective disorders. As sensory problems are highly prevalent in individuals with ASD and their siblings, and the occurrence of affective disorders is elevated in parents of children with ASD, investigating sensory symptoms in parents is important both from clinical and theoretical standpoints.Fifty mothers of children and adolescents with ASD completed the Adolescent and Adult Sensory Profile (AASP). The AASP is a norm-referenced questionnaire that provides scores for four types of responses to sensory stimuli (sensory quadrants): hypo-sensitivity, hyper-sensitivity, sensation seeking, and sensory avoiding. Mothers' scores were compared with AASP norms. Ninety eight percent of mothers had sensory scores at least one standard deviation (SD) above the normative mean and 44% were two or more SDs above the mean for at least one sensory quadrant. This study provides the first evidence for sensory atypicality in parents of children with ASD. Further research is needed to elucidate the contribution of genetic and environmental influences on the expression of sensory problems in ASD.
    Molecular Autism 04/2014; 5(1):26. DOI:10.1186/2040-2392-5-26 · 5.49 Impact Factor
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    • "To contrast these results, one recent study provided a lower estimate of heritability (37%) but with wide confidence intervals (CI) (8–84%) (Hallmayer et al., 2011). As many as 15% of cases may be attributable to rare genetic factors like de novo mutations, rare copy number variations (CNVs) or chromosomal abnormalities but several common variants including CNVs and single nucleotide polymorphisms (SNPs) have also been strongly linked to autism (Cook and Scherer, 2008; Freitag et al., 2010; Devlin and Scherer, 2012). The contribution of rare and common variants to autism and their possible interactions remain to be determined, but available evidence suggests that common variants, despite each not being causal, increase the susceptibility to the disorder (Abrahams and Geschwind, 2008; Klei et al., 2012; Stein et al., 2013). "
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    ABSTRACT: Autism spectrum disorders (ASD) are highly heritable complex neurodevelopmental disorders with a 4:1 male: female ratio. Common genetic variation could explain 40-60% of the variance in liability to autism. Because of their small effect, genome-wide association studies (GWASs) have only identified a small number of individual single-nucleotide polymorphisms (SNPs). To increase the power of GWASs in complex disorders, methods like convergent functional genomics (CFG) have emerged to extract true association signals from noise and to identify and prioritize genes from SNPs using a scoring strategy combining statistics and functional genomics. We adapted and applied this approach to analyze data from a GWAS performed on families with multiple children affected with autism from Autism Speaks Autism Genetic Resource Exchange (AGRE). We identified a set of 133 candidate markers that were localized in or close to genes with functional relevance in ASD from a discovery population (545 multiplex families); a gender specific genetic score (GS) based on these common variants explained 1% (P = 0.01 in males) and 5% (P = 8.7 × 10(-7) in females) of genetic variance in an independent sample of multiplex families. Overall, our work demonstrates that prioritization of GWAS data based on functional genomics identified common variants associated with autism and provided additional support for a common polygenic background in autism.
    Frontiers in Genetics 02/2014; 5:33. DOI:10.3389/fgene.2014.00033
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