Genomic Imbalances in Autism

Summary

Principal Investigator: Susan Christian
Abstract: Chromosomal abnormalities associated with autism or autism spectrum-disorders have been reported in 56 different regions involving all 22 autosomes plus both sex chromosomes. The completion of the mapping of the human genome has enabled the development of new whole genome BAG microarrays that allow simultaneous examination of the entire human genome for chromosomal abnormalities involving changes in dosage (i.e. deletions or duplications). This technique is termed array comparative genomic hybridization (aCGH). Routine cytogenetics has a resolution of approximately 3-4 MB while the whole genome microarrays have a resolution of -150 kb. The availability of these microarrays allows for the first time the ability to screen for constitutional chromosomal abnormalities related to autism on a whole genome scale. The hypothesis to be tested is that chromosomal imbalances detected using aCGH will identify both large abnormalities plus new smaller abnormalities that were previously undetectable using older techniques. Aim #1)Array CGH using a 6k microarray will be performed on 800 subjects with autism or autism spectrum disorder. To determine whether the abnormality is associated with autism, a case control study using 800 normal controls will also be perfomed. Aim #2) In silico analysis of the abnormal regions identified in aim #1 will be performed using the UCSC genome bioinformatics website. The regions will be characterized for the presence of microsatellites for confirmation studies, candidate genes, predicted genes and regions of strong conservation between species. Aim #3) All subjects that contain a region or regions with abnormal dosage using array CGH will be confirmed using both molecular and cytogenetic techniques. Microsatellite analysis of the child and both parents will be used to confirm the presence and size of the abnormality and the parental origin for potentially imprinted regions. Aim #4) Statistical analysis. The chisquared contingency table test will be performed and the significance of the result assessed using a Monte Carlo approach to determine the statististical significance of chromosomal imbalances. These data will be valuable in both identifying polymorphic variants in normal human control samples and also identifying chromosomal dosage imbalances that are associated with autism.
Funding Period: 2005-08-15 - 2010-02-28
more information: NIH RePORT

Top Publications

  1. ncbi Recurrent 16p11.2 microdeletions in autism
    Ravinesh A Kumar
    Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA
    Hum Mol Genet 17:628-38. 2008
  2. pmc Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder
    Susan L Christian
    Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA
    Biol Psychiatry 63:1111-7. 2008
  3. ncbi Genetics of autism spectrum disorders
    Ravinesh A Kumar
    Department of Human Genetics, University of Chicago, 920 East 58th Street, MC0077, Chicago, IL 60637, USA
    Curr Neurol Neurosci Rep 9:188-97. 2009
  4. ncbi Copy number and sequence variants implicate APBA2 as an autism candidate gene
    Timothy D Babatz
    Department of Human Genetics, University of Chicago, Chicago, Illinois 60637 5415, USA
    Autism Res 2:359-64. 2009
  5. pmc Association and mutation analyses of 16p11.2 autism candidate genes
    Ravinesh A Kumar
    Department of Human Genetics, The University of Chicago, Chicago, Illinois, USA
    PLoS ONE 4:e4582. 2009
  6. pmc A de novo 1p34.2 microdeletion identifies the synaptic vesicle gene RIMS3 as a novel candidate for autism
    Ravinesh A Kumar
    Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA
    J Med Genet 47:81-90. 2010

Detail Information

Publications7

  1. ncbi Recurrent 16p11.2 microdeletions in autism
    Ravinesh A Kumar
    Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA
    Hum Mol Genet 17:628-38. 2008
    ..Our work reports the first frequency, breakpoint, bioinformatic and phenotypic analyses of a de novo 16p11.2 microdeletion that represents one of the most common recurrent genomic disorders associated with autism to date...
  2. pmc Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder
    Susan L Christian
    Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA
    Biol Psychiatry 63:1111-7. 2008
    ..e., microdeletions and microduplications that are undetectable at the level of traditional cytogenetic analysis, allows the potential association of submicroscopic chromosomal imbalances and human disease...
  3. ncbi Genetics of autism spectrum disorders
    Ravinesh A Kumar
    Department of Human Genetics, University of Chicago, 920 East 58th Street, MC0077, Chicago, IL 60637, USA
    Curr Neurol Neurosci Rep 9:188-97. 2009
    ..Although great progress has been made in autism genetics, the molecular bases of most ASDs remains enigmatic...
  4. ncbi Copy number and sequence variants implicate APBA2 as an autism candidate gene
    Timothy D Babatz
    Department of Human Genetics, University of Chicago, Chicago, Illinois 60637 5415, USA
    Autism Res 2:359-64. 2009
    ..The co-occurrence of two nonsynonymous mutations in both affected siblings in a single family, each transmitted from a different unaffected parent, suggest a role for APBA2 mutations in rare individuals with ASD...
  5. pmc Association and mutation analyses of 16p11.2 autism candidate genes
    Ravinesh A Kumar
    Department of Human Genetics, The University of Chicago, Chicago, Illinois, USA
    PLoS ONE 4:e4582. 2009
    ..2 that contains 24 genes represents the second most frequent chromosomal disorder associated with autism. The role of common and rare 16p11.2 sequence variants in autism etiology is unknown...
  6. pmc A de novo 1p34.2 microdeletion identifies the synaptic vesicle gene RIMS3 as a novel candidate for autism
    Ravinesh A Kumar
    Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA
    J Med Genet 47:81-90. 2010
    ..3 Mb microdeletion on chromosome 1p34.2p34.3. The hypothesis is tested that this microdeletion contains one or more genes that underlie the autism phenotype in this child and in other children with autism spectrum disorders...