Research discoveries to diagnostic panels an update TPMI

Research discoveries to diagnostic panels  an update TPMI

Research discoveries to diagnostic panels an update TPMI Research Day October 8, 2015 Darren D. ORielly, Ph.D., FCCMG Director, Molecular Genetics Laboratory, Eastern Health Director, Translational Genomics Laboratory, Faculty of Medicine, MUN Research Scientist, Faculty of Medicine, MUN Adjunct Professor, School of Pharmacy, MUN Overview What are diagnostic panels? Translational Genomics Laboratory Personnel Equipment Available genomic services Translational Projects current & short-term Diagnostic panels Multi-variant or multi-gene in design Very cost-effective and time-efficient approach

Provide more information to clinicians Enhance clinical decision making Translational lab personnel Director Darren ORielly Ph.D., FCCMG Research Assistant (RA) Cindy Penny Translational Genomics Laboratory Working Group Darren ORielly Ph.D., FCCMG Terry Lynn Young Ph.D. Cindy Penny - RA Jim Houston Experienced RA in Young Lab Dianne Codner Experienced RA in Rahman/ORielly Lab Sonya Sheaves Molecular Genetics Technologist Translational lab equipment Uniplex targeted genotyping ABI 7500 Real-time PCR system x 2 Multiplex targeted genotyping Sequenom MassArray 4 system Luminex 100/200 system

Translational lab equipment Sanger sequencing, microsatellite and fragment analysis ABI 3500XL Copy number detection and gene expression analysis Agilent TapeStation Agilent Microarray system Translational lab equipment Next-generation sequencing Ion Chef (liquid handler) Ion Torrent PGM (targeted analysis) Ion Torrent Proton (exome, genome) Genomic services Available now: Targeted uniplex genotyping Targeted multiplex genotyping Sanger sequencing Available in coming months:

Targeted NGS panels Whole-exome sequencing Genome-wide CNV analysis Projects 2014 to 2016 Stargardt disease recurrent mutation panel HLA-B*27 tagSNP screening assay Hearing loss targeted mutation assays Sudden cardiac death recurrent mutation panel Comprehensive genetic testing for CRC: Recurrent mutation panel Custom NGS panel and custom exon deletion/duplication assay MSI assay for CRC (5 markers) MLH1 hypermethylation & BRAF V600E assay Oncomine Focus assay Projects 2014 to 2016 Stargardt disease recurrent mutation panel HLA-B*27 tagSNP screening assay Hearing loss targeted mutation assays Sudden cardiac death recurrent mutation panel

Comprehensive genetic testing for CRC: Recurrent mutation panel Custom NGS panel and custom exon deletion/duplication assay MSI assay for CRC (5 markers) MLH1 hypermethylation & BRAF V600E assay Oncomine Focus assay Stargardt disease mutation panel A diagnostic panel of 20 mutations in ABCA4 previously identified in the NL population and known to cause Stargardt disease is currently being validated. Validation expected to be completed by end of December 2015. Nucleotide Change c.67-1delG (IVS2) c.455G>A c.634C>T c.1522C>T c.2564G>A c.2588G>C c.3064G>A c.3322C>T

c.3323G>A c.4139C>T c.4163T>C c.4222T>C c.4469G>A c.4537delC c.4577C>T c.4918C>T c.5461-10T>C (IVS38) c.5714+5G>A (IVS40) c.6089G>A c.6449G>A Amino acid change # of alleles Exon rs# splice site

p.Arg152Gln P.Arg212Cys p.Arg508Cys p.Trp855X p.Gly863Ala p.Glu1022Lys p.Arg1108Cys p.Arg1108His p.Pro1308Leu p.Leu1388Pro p.Trp1408Arg p.Cys1490Tyr p.Gln1513Argfs*13 p.Thr1526Met p.Arg1640Trp splice site? splice site 3 3/11 1 2

5 2/4 1 3 1 4 8 1 2 1 3 1 12 31 2 5 6 11 16 17 21

22 22 28 28 28 30 30 31 35 38 40 rs67-1delG rs82646862 rs61750200 rs138157885 rs6175406 rs76157638 rs61749459 rs61750120 rs61750121 rs61750130

rs61750131 rs61750135 rs61751402 rs4537delC rs61750152 rs61751404 rs1800728 rs61751407 p.Arg2030Gln p.Cys2150Tyr 1 1 44 47 rs61750641 rs61751384 Cardiomyopathy screen panel

A diagnostic panel of 20 mutations previously identified in the NL population and known to cause cardiomyopathies is currently being validated. Projects 2014 to 2016 Stargardt disease recurrent mutation panel HLA-B*27 tagSNP screening assay Hearing loss targeted mutation assays Sudden cardiac death recurrent mutation panel Comprehensive genetic testing for CRC: Recurrent mutation panel Custom NGS panel and custom exon deletion/duplication assay MSI assay for CRC (5 markers) MLH1 hypermethylation & BRAF V600E assay Oncomine Focus assay Recurrent mutation panel A panel of >20 variants strongly associated with hereditary CRC will be developed as a first-pass test for individuals at moderate- or high-risk of CRC. Design of the panel is expected to be complete by the end of

November 2015 and validation finished by the end of March 2016. FAP APC IVS3-1G>A (Twillingate mut'n) FAP APC 694C>T (R236X) exon 6 ?694 or 649 FAP APC 3067-3068insA FAP

APC exon 12 1622-1623insCA FAP APC (1309)delAAAGA FAP APC (1061)delACAAA HNPCC MSH2 Fam C

HNPCC MSH2 Exon 8 deletion HNPCC MSH2 Exons 4-16 deletion HNPCC MSH2 c.1661G>C HNPCC MSH2

c.488T>G (p.V163G) HNPCC MLH1 V49E (c.146T>A) HNPCC MLH1 C77R / c.229T>C HNPCC MLH1 p.Ala128LysfsX22 (dupl exons 3&4) HNPCC

MSH6 c.3557-1G>A HNPCC MSH6 c.3514dupA HNPCC MSH6 c. 3640G>T / p.E1214X HNPCC PMS2 c.736_741del6ins12

HNPCC PMS2 c.593_593insT HNPCC PMS2 c.903+1G>A HNPCC PMS2 Exon 6-8 deletion HNPCC PMS2

exon 10 deletion MYH MYH MYH MYH Y165C/G382D 891+3A->C MYH MYH c.536A>G homoz Hereditary cancer NGS panel A panel of ~20 genes strongly associated with hereditary cancer (CRC/BOC) will be developed using NGS as a test for

individuals at moderate- or high-risk of CRC who test negative with the targeted Sequenom panel. BRCA1, BRCA2, CDH1, STK11, PTEN, PALB2, TP53, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, MYH, SMAD4, BMPR1A, CHEK2 and ATM (including a few other genes TBD) Design of the NGS panel is expected to be complete by the end of December 2015 and validation finished by the end of May 2016. Hereditary cancer exon deletion/duplication assay A custom Agilent microarray will be designed covering all exons for all genes included in the custom hereditary cancer NGS panel. The array design is expected to be completed by the end of January 2016 and the validation finished by the end of August 2016. CRC tumour genetic testing MSI panel 5 microsatellite markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27)

First somatic test developed and validated by the Translational Genomics Laboratory MLH1 methylation assay & BRAF V600E assay Oncomine Focus NGS panel Targets relevant hotspots & gene fusions Design includes 52 genes targeted by oncology drugs (e.g., KRAS, BRAF, EGFR) Validation expected to be completed by end of 2016. Projects 2017 to 2018 Cardiomyopathy targeted multi-gene NGS panel Hematological oncology multi-gene NGS panel Hereditary deafness multi-gene NGS panel Inherited disease multi-gene NGS panel Clinical whole-exome NGS panel Acknowledgements

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