HGM 2011 - Dubai, UAE
EVAN EICHLER - Abstract
|
Evan E. Eichler
|
Structural variation of the genome is an important aspect in our understanding of human disease and susceptibility to disease. This presentation will focus on the genome-wide discovery, analysis and distribution of copy-number and structural variants within the normal human population and a population of children with intellectual disability. Our analysis will be based on a study of 15,732 children with autism, intellectual disability and congenital heart defects compared to 8,720 adult controls. I will show how high-quality sequence data can be used to predict regions associated with genomic instability as well as the discovery of the molecular basis for more complex neurocognitive disease based on a genomic hotspot model of rare and recurrent copy-number variants. I will present a two-hit CNV model to explain variability in disease phenotypes and show how the evolution of diverse structural haplotypes can act as a premutation state predisposing to recurrent rearrangement. I will contrast these results with more recent exome sequencing from a modest number of sporadic parent-child trios where offspring are diagnosed with autism and/or developmental delay. Our analyses suggest that rare CNVs are collectively common in the population and the presence of multiple events may help to explain the variability in disease manifestation. Combined with exome-based sequencing of patients, we predict that ~45% of sporadic cases of disease may be explained. The analyses are converging on a finite number of neurodevelopmental pathways where gene dosage imbalance in the heterozygous state is sufficient to create a neurological disease state. |
|
|
|
|
|
Sheikh Hamdan Bin Rashid Al Maktoum |
|
|
Human Genome Organisation |
|
Centre for Arab Genomic Studies |
