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Identifying autism loci and genes by tracing recent shared ancestry.

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.

Pubmed ID: 18621663

Authors

  • Morrow EM
  • Yoo SY
  • Flavell SW
  • Kim TK
  • Lin Y
  • Hill RS
  • Mukaddes NM
  • Balkhy S
  • Gascon G
  • Hashmi A
  • Al-Saad S
  • Ware J
  • Joseph RM
  • Greenblatt R
  • Gleason D
  • Ertelt JA
  • Apse KA
  • Bodell A
  • Partlow JN
  • Barry B
  • Yao H
  • Markianos K
  • Ferland RJ
  • Greenberg ME
  • Walsh CA

Journal

Science (New York, N.Y.)

Publication Data

July 11, 2008

Associated Grants

  • Agency: NIMH NIH HHS, Id: 1K01MH71801
  • Agency: NIMH NIH HHS, Id: 1K23MH080954-01
  • Agency: NIMH NIH HHS, Id: 1R01 MH083565
  • Agency: NICHD NIH HHS, Id: 5P30HD018655-26
  • Agency: NINDS NIH HHS, Id: 5R01NS048276-05
  • Agency: NIMH NIH HHS, Id: K01 MH071801
  • Agency: NIMH NIH HHS, Id: K01 MH071801-04
  • Agency: NIMH NIH HHS, Id: K01 MH071801-05
  • Agency: NIMH NIH HHS, Id: K23 MH080954
  • Agency: NIMH NIH HHS, Id: K23 MH080954-01
  • Agency: NIMH NIH HHS, Id: MH64547
  • Agency: NHGRI NIH HHS, Id: N01-HG-65403
  • Agency: NIMH NIH HHS, Id: R01 MH083565
  • Agency: NINDS NIH HHS, Id: R01 NS048276
  • Agency: NINDS NIH HHS, Id: R01 NS048276-01
  • Agency: NINDS NIH HHS, Id: R01 NS048276-02
  • Agency: NINDS NIH HHS, Id: R01 NS048276-03
  • Agency: NINDS NIH HHS, Id: R01 NS048276-04
  • Agency: NINDS NIH HHS, Id: R01 NS048276-05
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Autistic Disorder
  • Brain
  • Cadherins
  • Chromosome Mapping
  • Consanguinity
  • Female
  • Gene Deletion
  • Gene Dosage
  • Gene Expression Regulation
  • Genes, Recessive
  • Genetic Predisposition to Disease
  • Homozygote
  • Humans
  • Lod Score
  • Male
  • Mutation
  • Neurons
  • Oligonucleotide Array Sequence Analysis
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Rats
  • Sodium-Hydrogen Antiporter
  • Transcription Factors