Whole Exome Sequencing in 19 IA Families Author

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Whole Exome Sequencing in 19 IA Families Author : Updated : Ali Kemal Ozturk,

Whole Exome Sequencing in 19 IA Families Author : Updated : Ali Kemal Ozturk, M. D. , PGY-4 06/20/2010 333 Cedar Street New Haven, Connecticut 06510

1. Genetic Variants of IA Genetics of IA Common Variants OR 1. 1 -1.

1. Genetic Variants of IA Genetics of IA Common Variants OR 1. 1 -1. 5, MAF >1% Rare Variants OR>2, MAF <0. 1%

2. Why Study Rare Variants? Ø Analysis of protein function Ø Pathway analysis Ø

2. Why Study Rare Variants? Ø Analysis of protein function Ø Pathway analysis Ø Potential to understand both rare and common forms of disease Ø Potential for pre-clinical diagnosis Ø Targeted novel therapies

3. Linkage Analysis GGTAACCCTGAG GGTAAACCTGAG SNP

3. Linkage Analysis GGTAACCCTGAG GGTAAACCTGAG SNP

4. IA 20: 1 p 34 -36 Nahed et al, Am J Hum Genet.

4. IA 20: 1 p 34 -36 Nahed et al, Am J Hum Genet. 2005 Jan; 76(1): 172 -9. Epub 2004 Nov 11.

5. IA 20: 1 p 34 -36 Nahed et al, Am J Hum Genet.

5. IA 20: 1 p 34 -36 Nahed et al, Am J Hum Genet. 2005 Jan; 76(1): 172 -9. Epub 2004 Nov 11.

6. IA 20: 1 p 34 -36 Nahed et al, Am J Hum Genet.

6. IA 20: 1 p 34 -36 Nahed et al, Am J Hum Genet. 2005 Jan; 76(1): 172 -9. Epub 2004 Nov 11.

7. IA 20: 1 p 34 -36 From the UCSC Genome Browser: http: //genome.

7. IA 20: 1 p 34 -36 From the UCSC Genome Browser: http: //genome. ucsc. edu

8. IA 100 and IA 101: 11 q 24 and 14 q 23 -31

8. IA 100 and IA 101: 11 q 24 and 14 q 23 -31 Ozturk et al, Stroke. 2006 Apr; 37(4): 1021 -7. Epub 2006 Feb 23.

9. IA 100 and IA 101: 11 q 24 and 14 q 23 -31

9. IA 100 and IA 101: 11 q 24 and 14 q 23 -31 Ozturk et al, Stroke. 2006 Apr; 37(4): 1021 -7. Epub 2006 Feb 23.

10. IA 42

10. IA 42

11. IA 42 - Linkage Unpublished data

11. IA 42 - Linkage Unpublished data

12. All Linkage- Should we continue? Nahed et al, Neurosurgery. 2007 Feb; 60(2): 213

12. All Linkage- Should we continue? Nahed et al, Neurosurgery. 2007 Feb; 60(2): 213 -25; discussion 225 -6. Review.

13. Limitations Ø Family size and number Ø Incomplete penetrance Ø Phenocopies Ø Locus

13. Limitations Ø Family size and number Ø Incomplete penetrance Ø Phenocopies Ø Locus heterogeneity Ø Candidate gene sequencing

14. Whole Exome Sequencing Ø Routine whole genome sequencing is still not practical ØThere

14. Whole Exome Sequencing Ø Routine whole genome sequencing is still not practical ØThere approx. 180, 000 exons in the human genome (30 megabases) Ø Protein coding regions comprise 1% of the human genome Ø It is estimated that 85% of disease causing mutations reside in protein coding regions

15. Whole Exome Sequencing

15. Whole Exome Sequencing

16. 19 IA Pedigrees

16. 19 IA Pedigrees

17. Algorithm for Variant Detection Exome capture of 19 IA familes QC Data Analysis

17. Algorithm for Variant Detection Exome capture of 19 IA familes QC Data Analysis Sanger confirmation Filter against public datasets Linkage interval variants Familial Co-segregation Genes with multiple hits Screen controls and additional IA pts

18. Thank you Kaya Bilguvar Mehmet Bakircioglu Tanyeri Barak Winson Ho Katsuhito Yasuno Murim

18. Thank you Kaya Bilguvar Mehmet Bakircioglu Tanyeri Barak Winson Ho Katsuhito Yasuno Murim Choi Angeliki Louvi Shrikant Mane Matthew State Richard Lifton Murat Gunel Yale Department of Neurosurgery

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