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Solving Clinical Problems With Genomic Technologies

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Solving Clinical Problems With Genomic Technologies

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    1. Solving Clinical Problems With Genomic Technologies

    2. Genohype

    3. Genomic Strengths BC has world-class genomic technology. Physicians in BC are applying this technology to important clinical problems. You can do this, too.

    4. Genomic Strengths

    5. Genomics Provides: An inside-out approach that complements the standard outside-in approach to understanding disease A way of looking at the entire genome as a whole rather than one gene at a time

    6. Patient 1 Normal pregnancy and birth Severe mental retardation No speech Seizures Short stature Asthenic habitus Dysmorphic features

    7. Patient 1 Normal chromosomes Normal biochemical studies Blood amino acids, lactate, ammonia, acylcarnitine profile, biotinidase, TFIF Urine organic acids, MPS, oligosaccharides, purines and pyrimidines MRI: Brain malformation

    8. Family 1

    9. Illumina SNP Typing Single Nucleotide Polymorphisms 1 every ~1200 bp (~5M/person) > 6,200,000 validated SNPs

    10. Illumina SNP Typing Single Nucleotide Polymorphisms 1 every ~1200 bp (~5M/person) > 6,200,000 validated SNPs

    11. Illumina SNP Typing allele-specific oligos coated on beads 1536 bead types 50,000 beads put into a well 96 well plate

    12. Illumina SNP Typing

    13. Illumina SNP Typing Linkage studies Association studies Case-control Family-based Epigenomics

    14. Family 1

    15. Family 1 Linkage narrows region to 4,900,000 bp 240 known genes with 866 exons One mutation

    16. Solexa Sequencing

    17. Solexa Sequencing

    18. Solexa Sequencing >1Gb of sequence per run Applications: DNA resequencing genomic structural variation metagenomics RNA expression epigenomics

    19. Family 1

    20. Family 1 1st Results 117 amplicons of ~8kb each 326 exons covered 100% 14 exons partially covered

    21. Patient 2 February 2005: 10 y/o female presents at BCCH with abdominal mass Biopsy confirmed diagnosis of neuroblastoma Child began chemotherapy with protocol that includes doxorubicin

    22. Patient 2 August 2005: Remission achieved, chemotherapy well tolerated Prior to last cycle, child received routine CT scan During scan developed ventricular tachycardia and cardiogenic shock

    23. Patient 2 Child intubated, rushed to ICU Echocardiogram showed marked cardiac dysfunction with virtually no cardiac output

    24. Patient 2 August-September 2005: Child on ECMO, remained in ICU Final chemotherapy cycle not given Child remains in remission, on cardiac medication with limited physical activity

    25. Anthracycline Cardiotoxicity Anthracyclines widely-used chemotherapeutic agents breast cancer leukemia lymphoma Neuroblastoma Osteosarcoma Wilm’s tumour

    26. Anthracycline Cardiotoxicity 7-10% of patients severely affected Up to 33% moderately affected Dose-dependent, but some susceptible at very low doses

    27. Anthracycline Cardiotoxicity Damage permanent – life-long disability High mortality – up to 61% Increased risk for children <15 yrs, esp. < 4 yrs B.C. Children’s Hospital: 17.9% since Sept. 2006

    28. Anthracycline Cardiotoxicity Why does one child with neuroblastoma treated with anthracyclines end up in the ICU with congestive heart failure, while another child treated with the same dose has no cardiac damage?

    29. Illumina SNP Typing

    30. Anthracycline Cardiotoxicity Case-Control Study Target : 100 cases with anthracyline cardiotoxicity, 400 drug-matched controls Current: 78 cases , 313 controls

    31. Anthracycline Cardiotoxicity Key transporters of drug out of heart cells Decreased activity

    32. Anthracycline Cardiotoxicity Goal 1-hour bedside DNA cheek swab test for SNPs before treatment If results show high risk for anthracycline cardiomyopathy, start chemotherapy with 25% dose Result: patient survives cancer and treatment

    33. Patient 3 Male, age 9.5, with severe language impairment and autistic features Normal pregnancy and delivery Normal growth Asthma

    34. Patient 3 Mild dorsal scoliosis Vertebral fusions, 13th rib on left, bifid ribs Normal head CT Cytogenetics: Normal 46,XY

    35. Array Genomic hybridization

    36. Array Genomic hybridization Much higher resolution

    37. Patient 3 ~320 kb deletion at Chr 2p16.3

    38. Patient 3

    39. Patient 3

    40. NRXN1 Cell adhesion molecules and receptors in nervous system Involved in synapse formation Larger deletions of region associated with autism in previous studies

    41. BCCGN

    42. BCCGN Shelin Adam 604 875 2000 ext. 6063 ashelin@interchange.ubc.ca Lesley Phillips 604 875 2000 ext. 5980 lesleyp@interchange.ubc.ca Here is our contact information. Does anybody have any questions?Here is our contact information. Does anybody have any questions?

    43. Acknowledgements Patient 1: Neal Boerkoel, Christele du Souich, Margot Van Allen, Colin Ross, Tesa Severson, Marco Marra Patient 2: Rod Rassekh, Paul Rogers, Colin Ross, Michael Hayden, Bruce Carleton Patient 3: Farah Zahir, Nicole Fernandes, Agnes Baross, Allen Delaney, Patrice Eydoux, Trevor Pugh Here is our contact information. Does anybody have any questions?Here is our contact information. Does anybody have any questions?

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