Article

A high-density SNP genome-wide linkage scan in a large autism extended pedigree.

Department of Psychiatry, University of Utah, Salt Lake City, UT, USA.
Molecular Psychiatry (Impact Factor: 15.15). 03/2008; 14(6):590-600. DOI: 10.1038/mp.2008.14
Source: PubMed

ABSTRACT We performed a high-density, single nucleotide polymorphism (SNP), genome-wide scan on a six-generation pedigree from Utah with seven affected males, diagnosed with autism spectrum disorder. Using a two-stage linkage design, we first performed a nonparametric analysis on the entire genome using a 10K SNP chip to identify potential regions of interest. To confirm potentially interesting regions, we eliminated SNPs in high linkage disequilibrium (LD) using a principal components analysis (PCA) method and repeated the linkage results. Three regions met genome-wide significance criteria after controlling for LD: 3q13.2-q13.31 (nonparametric linkage (NPL), 5.58), 3q26.31-q27.3 (NPL, 4.85) and 20q11.21-q13.12 (NPL, 5.56). Two regions met suggestive criteria for significance 7p14.1-p11.22 (NPL, 3.18) and 9p24.3 (NPL, 3.44). All five chromosomal regions are consistent with other published findings. Haplotype sharing results showed that five of the affected subjects shared more than a single chromosomal region of interest with other affected subjects. Although no common autism susceptibility genes were found for all seven autism cases, these results suggest that multiple genetic loci within these regions may contribute to the autism phenotype in this family, and further follow-up of these chromosomal regions is warranted.

0 Followers
 · 
195 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Why do some institutionalized children develop indiscriminate behavior (IB) while others do not? Considering children with Williams syndrome (WS) may provide an answer because IB has been observed routinely among individuals with this rare genetic neurodevelopmental disorder. By conceiving WS as a natural genetic model that mimics the indiscriminate phenotype and, more importantly, is associated with the deletion of genes in a specific region, we propose an integrative conceptual framework that underscores the dynamic developmental interplay between genes, endophenotypes, and environment. In this article, we consider the etiology of IB among institutionalized children, which emphasizes environmental factors, followed by the effect of such behavior on WS children's hypersociability, which highlights the crosstalk between genes and neuropsychological features in programming their distinctive social‐emotional and behavioral phenotype. We propose new hypotheses regarding the etiopathogeny of IBs in institutionalized children, particularly the prediction of specific Gene × Environment interactions.
    Child Development Perspectives 09/2013; 7(3). DOI:10.1111/cdep.12036 · 1.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Autism is a childhood neurodevelopmental disorder with high heterogeneity. Following our genome-wide associated loci with autism, we performed sequencing analysis of the coding regions, UTR and flanking splice junctions of AMPD1 in 830 Chinese autism individuals as well as 514 unrelated normal controls. Fourteen novel variants in the coding sequence were identified, including 11 missense variants and 3 synonymous mutations. Among these missense variants, 10 variants were absent in 514 control subjects, and conservative and functional prediction was carried out. Mitochondria activity and lactate dehydrogenase assay were performed in 5 patients' lymphoblast cell lines; p.P572S and p.S626C showed decreased mitochondrial complex I activity, and p.S626C increased lactate dehydrogenase release in medium. Conclusively, our data suggested that mutational variants in AMPD1 contribute to autism risk in Han Chinese population, uncovering the contribution of mutant protein to disease development that operates via mitochondria dysfunction and cell necrosis.
    European Archives of Psychiatry and Clinical Neuroscience 08/2014; DOI:10.1007/s00406-014-0524-6 · 3.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genome instability, epigenetic remodelling and structural chromosomal rearrangements are hallmarks of cancer. However, the coordinated epigenetic effects of constitutional chromosomal rearrangements that disrupt genes associated with congenital neurodevelopmental diseases are poorly understood. To understand the genetic-epigenetic interplay at breakpoints of chromosomal translocations disrupting CG-rich loci, we quantified epigenetic modifications at DLGAP4 (SAPAP4), a key post-synaptic density 95 (PSD95) associated gene, truncated by the chromosome translocation t(8;20)(p12;q11.23), co-segregating with cerebellar ataxia in a five generation family. We report significant epigenetic remodelling of the DLGAP4 locus triggered by the t(8;20)(p12;q11.23) translocation and leading to dysregulation of DLGAP4 expression in affected carriers. Disruption of DLGAP4 results in monoallelic hypermethylation of the truncated DLGAP4 promoter CpG island. This induced hypermethylation is maintained in somatic cells of carriers across several generations in a t(8;20) dependent-manner however, is erased in the germ cells of the translocation carriers. Subsequently, chromatin remodelling of the locus perturbed monoallelic expression of DLGAP4 mRNAs and non-coding RNAs in haploid cells having the translocation. Our results provide new mechanistic insight into the way a balanced chromosomal rearrangement associated with a neurodevelopmental disorder perturbs allele-specific epigenetic mechanisms at breakpoints leading to the deregulation of the truncated locus.
    Human Molecular Genetics 07/2014; 23(23). DOI:10.1093/hmg/ddu337 · 6.68 Impact Factor

Full-text (2 Sources)

Download
118 Downloads
Available from
May 17, 2014