HGM 2011 - Dubai, UAE
Christopher A. Walsh - Abstract
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Christopher A. Walsh
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An important unanswered question in genetics is how cognitive abilities are mapped onto genomes. Studies from many laboratories suggest that humans far exceed saturation mutagenesis? for mutations at all possible loci that govern the development of the brain. Many of these mutations create rare (<1 in 10,000 individuals affected) Mendelian syndromes, that are often recessively inherited, and typically most easily studied by analyzing families in which parents have distant shared ancestry. On the other hand, intellectual disability and autism collectively affect up to 2% of the population, yet causal genes are known only in a minority of patients. An increasing amount of data suggests that autism can arise from a heterogeneous collection of rare mutations, including syndromic forms (e.g., Fragile X or MECP2 mutations), rare quasi-Mendelian forms (NRXN1, SHANK3, or NLGN3/4 mutations), recurrent de novo copy number variants (CNV's, e.g., 22q11 deletions, 16p11.12 deletions or duplications, and 15p11 duplications) and other, diverse CNV's. In order to identify inherited mutations associated with autism, our collaborators have recruited >240 families with one or more children affected with autism (>40 with 2 or more affected children) in which the two parents share distant common ancestry, focusing recruitment on countries where cousin marriage is common (including Kuwait, Saudi Arabia, Turkey, Pakistan). Analysis of these families identified a lower incidence of large, de novo CNV's compared to comparable children with unrelated parents, consistent with an important role for inherited, recessive mutations in children whose parents share ancestry. Some autistic children showed homozygous deletions, inherited through both parents from a common ancestor, often involving noncoding DNA near genes involved in neurological function, and suggesting the importance of precise timing and patterns of gene expression. One gene (SCL9A9, a.k.a. NHE9) near a large deletion seen in a patient with autism with seizures also showed heterozygous point mutations in American children with autism and seizures. High throughput array capture, whole exome, and whole genome sequence analysis reveals additional mutations in unexpected pathways including chromatin regulation, gene expression, and neurometabolism, and also suggest ways in which quasi recessive genes may interact in ?complex' fashion. Supported by the NIMH, the Simons Foundation, the NLM Family Foundation and the Howard Hughes Medical Institute. |
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Sheikh Hamdan Bin Rashid Al Maktoum |
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Human Genome Organisation |
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Centre for Arab Genomic Studies |
