We will apply whole exome sequencing to discover mutations causing structural brain disease in a large cohort of patients from consanguineous union. Comprehensive discovery of mutations that cause brain malformations holds great promise for advancing understanding of determinants of brain development and function and its consequences including epilepsy, developmental delay, and motor deficits. Recently, abnormalities in cerebral development have also been linked to neuropsychiatric disorders, including autism. The search for brain malformation genes has been hampered by the lack of large well-characterized cohorts. Because structural brain disorders are uncommon in the general population but much more prevalent among the offspring of consanguineous union, these consanguineous patients are highly likely to have recessive disease caused by homozygous mutations. This has been confirmed for a number of structural brain abnormalities, which have identified neuronal guidance molecules and their receptors, as well as other genes that have illuminated novel functions in brain development. For this reason, we have assembled one of world's largest collections of patients with structural brain abnormalities who are products of consanguineous union. Among these, we chose a highly selective group of 250 independent families, confirmed to be consanguineous by high density SNP genotyping, for exome sequencing. These cases presumptively each represent a recessive form of disease, allowing efficient application of whole exome sequencing to discover causative mutations. The presumptive disease mutations are expected to be novel or rare homozygous mutations within segments homozygous by consanguineous descent. The finding of the identical homozygous mutation in affected sibs and independent mutations in the same gene in other cohort members will provide strong genetic evidence that disease loci have been identified, and further studies in animal models can confirm their significance. Because protein coding regions represent only ~1% of the human genome but account for ~85% of all mutations in diverse Mendelian disorders, it has long been recognized that selective sequencing of exons should be more efficient and cost effective than sequencing whole genomes. Moreover, in affected subjects from 1st cousin marriages, only ~10% of the genome is homozygous by descent, so the search for disease mutations is efficient, confined to 0.1% of the genome. Finally, detection of homozygous mutations is markedly easier, less error prone and requires lower depth of coverage than detection of heterozygous mutations. Based on these observations, we have implemented whole exome sequencing for gene discovery and shown its utility for this project. Consistent with the goals of this RFA, we are ready to proceed immediately with whole exome re-sequencing of 250 carefully selected consanguineous patients with structural brain abnormalities. Discovery of genes causing these abnormalities will allow fundamental mechanistic insights into brain development and potentially allow new therapeutic approaches to these and related neuropsychiatric disorders.
Structural brain abnormalities are a major cause of epilepsy, developmental delay and mental retardation. More subtle forms are associated with other neurodevelopmental disorders, including autism. We propose to use exomic sequencing to discover genes that cause brain malformations in a highly selective cohort of 250 independent families, confirmed to be consanguineous by high density SNP genotyping. Discovery of genes causing these abnormalities will allow fundamental mechanistic insights into brain development and potentially allow new therapeutic approaches to these and related neuropsychiatric disorders.
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