1. SCRIPPS GENOME ADVISER Galina Erikson Senior Bioinformatics Programmer The Scripps Translational Science Institute Scripps Translational Science Institute

2. As simple as uploading a file: genomics.scripps.edu/ADVISER/ Databases and Algorithms Molecular Diagnosis

3. Prior Knowledge Phenotype Associations GWAS Catalog Allele Frequency eQTL Databases Disease Ontology Cancer Genes Prior Cancer Observations Genomic Elements Known Genes Location Relative to Gene Protein Domains Transcription Factor Binding Sites Conserved Elements miRNA Binding Sites miRNA Genes Splice Sites Splicing Enhancers/Silencers Prediction of Impact Coding Impact Nonsynonymous Impact Prediction Protein Domain Impact Prediction TFBS Impact Scores Nucleotide Conservation microRNA BS Impact Splicing Changes Binding Energy Truncation Impact Prediction miRNA Target Changes Linking Elements Phase Information Molecular Function Biological Processes Biological Pathways Synthesis Predicted Disease Variants Predicted Disease Genes …… A solution: Whole Genome Annotation and Prediction genomics.scripps.edu/ADVISER /

4. Filtered variant of interest: rs73885319

5. Initial Subject at Scripps: IDIOM Study, Patient #9 Presentation 9-yr-old European female, lifelong history Hypotonia Developmental delays Cognitive impairment Intermittent agitation MRI showed subtle asymmetric volume loss in left hippocampus Motor milestones were delayed Onset of generalized tonic-clonic seizures (GTCS) was at 4.75 years of age Sequencing Quartet exome sequencing WES: SureSelect, 100x coverage, 93-95% with 10+ reads WES Variant Summary: 101,797 SNPs & indels 18,475 Rare variants, <1% allele frequency 1,053 Nonsynonymous, truncating, or splice site 2 De novo inheritance 3 Homozygous or compound heterozygous

6. Variant files format accepted: VCF, CGI, BED, CNVnator

7. User accounts and unregistered uploads

8. Select file to upload

9. You will receive an email once results the file is annotated

10. SG-ADVISER UI

11. Load in the annotated SUMMARY file

12. Loading File – multithreading – progress bar Loads 3GB file in 17 seconds. The scientist can see the first 500 lines and/or see next pages while the file is still loading

13. 12 custom filters

14. 25 category 1 variants

15. Load genotypes from VCF file

16. None of the category 1 variants are homozygous, De- novo or compound heterozygous in proband.

17. IDIOM filter

18. De novo KCNB1 mutation

19. Epileptic Encephalopathy

20. Funding SG-ADVISER, NHGRI 1 U01 HG006476-01 NIH/NCRR flagship CTSA grant (Eric Topol, MD) Scripps Genomic Medicine Division of Scripps Health Schaeffer Family Foundation / Warren Foundation / Zarrow Foundation Acknowledgements Scripps Translational Science Institute Bill Shipman Ali Torkamani, PhDPhillip Pham

21. Evening tool demonstrations