Identifying Autism Loci and Genes by Tracing Recent Shared Ancestry

Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Science (Impact Factor: 33.61). 08/2008; 321(5886):218-23. DOI: 10.1126/science.1157657
Source: PubMed


To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the
role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely
mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that
underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of “homozygosity
mapping” in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural
activity may be a mechanism common to seemingly diverse autism mutations.

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    • "This puts MDGA2 in line with other neuronal cell adhesion molecules of the immunoglobulin family, such as RESEARCH ARTICLE Biology Open (2015) 000, 1–9 doi:10.1242/bio.20148482 contactins, NRCAM, CADM1 and LRFN5 that are implicated in axon migration and guidance and were associated with autism (Berglund et al., 1999; Fernandez et al., 2004; Glessner et al., 2009; Roohi et al., 2009; Cottrell et al., 2011; Morrow et al., 2008; van Daalen et al., 2011; Bonora et al., 2005; Marui et al., 2009; Zhiling et al., 2008; de Bruijn et al., 2010). In summary, the association of truncated MDGA2 variants with ASD, and the notion that a number of neuronal cell adhesion factors are implicated in ASD, supports also a role of human MDGA2 as a cell adhesion molecule important in neuronal positioning and axon guidance. "
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    ABSTRACT: The formation of functional neuronal circuits relies on accurate migration and proper axonal outgrowth of neuronal precursors. On the route to their targets migrating cells and growing axons depend on both, directional information from neurotropic cues and adhesive interactions mediated via extracellular matrix molecules or neighbouring cells. The inactivation of guidance cues or the interference with cell adhesion can cause severe defects in neuronal migration and axon guidance. In this study we have analyzed the function of the MAM domain containing glycosylphosphatidylinositol anchor 2A (MDGA2A) protein in zebrafish cranial motoneuron development. MDGA2A is prominently expressed in distinct clusters of cranial motoneurons, especially in the ones of the trigeminal and facial nerves. Analyses of MDGA2A knockdown embryos by light sheet and confocal microscopy revealed impaired migration and aberrant axonal outgrowth of these neurons; suggesting that adhesive interactions mediated by MDGA2A are required for the proper arrangement and outgrowth of cranial motoneuron subtypes. © 2015. Published by The Company of Biologists Ltd.
    Biology Open 01/2015; 4(2). DOI:10.1242/bio.20148482 · 2.42 Impact Factor
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    • "High-resolution molecular karyotyping is a powerful tool to identify a large number of DNA gains and losses that are associated with various neurological phenotypes, but the yield is typically <15%, and it rarely identifies single genes due to the nature of the assay (Miller et al., 2010). Morrow et al. used autozygosity mapping in nearly 90 consanguineous families with autism, followed by Sanger sequencing of candidate genes within the linked ROH, to identify five novel autism genes (Morrow et al., 2008). The lower yield of that study likely originates from the use of conventional sequencing methods, coupled with the potentially non-Mendelian behavior of autism genes. "
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    ABSTRACT: Neurogenetic disorders represent the largest category of Mendelian diseases in humans. They encompass a wide array of clinical presentations that range from the common e.g., intellectual disability (>1%) to the very rare, e.g., neurodegeneration with brain iron accumulation (one to three per 106) (Kalman et al., 2012 and Maulik et al., 2011). The highly prevalent involvement of the nervous system in many Mendelian disorders coincides with the observation that >80% of all human genes are expressed at some stage of brain development (Hawrylycz et al., 2012) and suggests that the brain is one of the most vulnerable organs to genetic perturbation. In fact high-resolution microarray analysis of the human genome reveals that intellectual disability is the common phenotypic denominator of genomic disorders that involve losses or gains of genes (Coe et al., 2012).
    Cell Reports 12/2014; 82(2). DOI:10.1016/j.celrep.2014.12.015 · 8.36 Impact Factor
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    • "Convincing statistical evidence for the role of rare recessive inherited variants in ASD risk comes from two recent studies that applied whole-exome sequencing to a cohort of consanguineous and/or multiplex families and to ASD cases using a population-based approach [8,9]. The contribution of recessive mutations to ASD heritability is supported by the success of homozygosity mapping to identify autism genes in consanguineous families [10], the use of homozygosity mapping as a powerful strategy for filtering whole-exome sequence data [11] and the identification that ASD probands display a much higher degree of haplotype sharing within overlapping homozygous regions compared to parental controls [12]. "
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    ABSTRACT: Background Autism spectrum disorder (ASD) is a highly heritable, neurodevelopmental condition showing extreme genetic heterogeneity. While it is well established that rare genetic variation, both de novo and inherited, plays an important role in ASD risk, recent studies also support a rare recessive contribution. Methods We identified a compound heterozygous deletion intersecting the CTNNA3 gene, encoding αT-catenin, in a proband with ASD and moderate intellectual disability. The deletion breakpoints were mapped at base-pair resolution, and segregation analysis was performed. We compared the frequency of CTNNA3 exonic deletions in 2,147 ASD cases from the Autism Genome Project (AGP) study versus the frequency in 6,639 controls. Western blot analysis was performed to get a quantitative characterisation of Ctnna3 expression during early brain development in mouse. Results The CTNNA3 compound heterozygous deletion includes a coding exon, leading to a putative frameshift and premature stop codon. Segregation analysis in the family showed that the unaffected sister is heterozygote for the deletion, having only inherited the paternal deletion. While the frequency of CTNNA3 exonic deletions is not significantly different between ASD cases and controls, no homozygous or compound heterozygous exonic deletions were found in a sample of over 6,000 controls. Expression analysis of Ctnna3 in the mouse cortex and hippocampus (P0-P90) provided support for its role in the early stage of brain development. Conclusion The finding of a rare compound heterozygous CTNNA3 exonic deletion segregating with ASD, the absence of CTNNA3 homozygous exonic deletions in controls and the high expression of Ctnna3 in both brain areas analysed implicate CTNNA3 in ASD susceptibility.
    Journal of Neurodevelopmental Disorders 07/2014; 6(1):17. DOI:10.1186/1866-1955-6-17 · 3.27 Impact Factor
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