Learning Objectives. Genomic Medicine and Primary Care. Clinical Applications of Genome-Level DNA Sequencing. Molecular Medicine.

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1 Presenter Disclosure Information 9:45 10:25am Genomic Medicine and Primary Care SPEAKER Wayne W. Grody, MD, PhD, FACMG, FCAP The following relationships exist related to this presentation: Wayne W. Grody, MD, PhD, FACMG, FCAP: No financial relationships to disclose. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Genomic Medicine and Primary Care Wayne W. Grody, M.D., Ph.D. Divisions of Medical Genetics and Molecular Diagnostics Departments of Pathology & Laboratory Medicine, Pediatrics, and Human Genetics UCLA School of Medicine Director, Molecular Diagnostic Laboratories and Clinical Genomics Center UCLA Medical Center Learning Objectives Summarize the latest genomic discoveries and technological innovation that are driving the implementation of companion diagnostics and genomic medicine Discuss the clinical utility of new molecular markers in various genetic diseases, cancers, and pharmacogenetic applications Examine the unique ethical, legal, psychosocial, regulatory and economic implications surrounding these developments, and their impact on patient access to personalized medicine offered by this powerful and diagnostic predictive technology Molecular Medicine One gene/one disease Genomic Medicine All genes/all diseases Clinical Applications of Genome-Level DNA Sequencing Diagnosis of rare or novel genetic disorders Identification of drug-able mutation targets in malignant tumors Noninvasive prenatal testing for aneuploidies and other genetic disorders Couple carrier screening for rare recessive disorders? Prenatal testing? Newborn screening? Predictive risk assessment in healthy individuals?

2 A Little Taste of the Challenge Ahead: Sequencing Experience With BRCA1&2 Complete sequencing of both genes in >600,000 people at Myriad Genetics alone >20,000 mutations and benign or uncertain variants identified Yet every week, detect new missense variants never seen before [B. Ward, personal communication] Grody et al., Genet. Med. (2001) ACMG RECOMMENDED CORE MUTATION PANEL FOR GENERAL POPULATION CF CARRIER SCREENING Classes of Novel/Unexpected Sequence Variants Identified by Whole Genome/Exome Sequencing F508 I507 G542X G551D W1282X N1303K R553X 621+1G>T R117H G>A A455E R560T R1162X G85E R334W R347P 711+1G>T G>A 2184delA 1078delT kbC>T G>A 3659delC I148T G>A Grody et al., Genet. Med. (2001) Missense variants of uncertain significance in known gene (VUS) Variants and deleterious mutations in unknown gene(s) (GUS) Variants and mutations in known but currently irrelevant genes (e.g., pharmacogenetic markers, recessive carrier states) Deleterious mutations in unintended target (e.g., BRCA mutations in a baby) NIH Task Force on Genetic Testing WGS Represents a Sea-Change in Clinical Laboratory Testing: For the first time, patients may need to choose beforehand what portions of the test results they wish to receive or not receive.

3 Informed Consent for Whole Genome Sequencing: Patient Choices Receive all information (CD, DVD?) Receive relevant/targeted information for patient s age for future for relatives Genet. Med Major Recommendations of the ACMG Incidental Findings Committee Mutations in a select list of high-penetrance, potentially lethal but actionable conditions must be sought and reported Same rules apply to sequencing of healthy parents in a trio or benign companion tissue when doing tumor sequencing These results are given to the ordering clinician who has responsibility for deciding which, when and how to convey to the patient The patient cannot opt out from receiving these incidental findings Disease Gene Panels for Next-Generation Sequencing Hypertrophic cardiomyopathy Dilated cardiomyopathy Hereditary arrhythmias (channelopathies) Retinitis pigmentosa Albinism Mental retardation DNA repair defects Skeletal dysplasias Disorders of sexual development Hearing loss EVOLUTION OF MOLECULAR GENETIC TESTING Single gene/single mutation Single gene/multiple mutation panel Multiple genes/multiple mutations Whole-gene sequencing Multiple whole-gene sequencing panel Whole-exome sequencing Whole-genome sequencing

4 Ethical Dilemmas of Whole Genome Sequencing Revelation of off-target mutations Many revealed disorders will have no prevention or treatment Revelation of nonpaternity, consanguinity, incest Costs of genetic counseling and follow-up Possible forensic uses of data Data storage and privacy Huge number of novel missense variants Clinical Genomics Board Molecular/genomic laboratory directors Laboratory technical staff Genomic bioinformaticists Clinical geneticists, pediatricians Genetic counselors Residents/fellows Ordering clinicians Case #1 17-year-old female with movement disorder (ataxia) since age 2 Carried longstanding diagnosis of juvenile ALS, but UCLA neurologists not convinced Case #1 RESULTS: One homozygous, probable disease-causing variant E359X in AAAS was detected. Other observed variants, within the primary gene list, are not convincingly demonstrated to be causal. INTERPRETATION: The data are consistent with a 46, XX female. There are 10 intervals greater than 5 Mb that are homozygous-by-descent, suggesting consanguinity. There is no evidence of any copy number abnormalities (gain or loss) involving an entire chromosome arm. The following primary gene list associated with the keyword(s) below was generated using the HGMD (Human Gene Mutation Database) Professional Version : Primary Gene List: ALAD, ALS2, ANG, APEX1, CDH13, CHGB, CHMP2B, CRYM, DAO, DCTN1, FIG4, FUS, GRN, LUM, OPTN, PARK7, PON1, PON2, PON3, PRPH, SOD1, FUS, VAPB, TARDBP, VCP, SETX, UBQLN2 Keywords: Amyotrophic lateral sclerosis, ALS, ataxia Protein changing variants within the homozygous intervals: Within the homozygous intervals, the following four probable disease-causing variants were found. Of these, a nonsense mutation expected to cause protein truncation in gene AAAS seems to correlate with patient s clinical symptoms. Defects in this gene are reported to cause achalasia-addisonianism-alacrima syndrome (AAAS or Triple A syndrome ) [Ref 2]. Clinical Whole-Exome Sequencing: Lessons Learned From the First Three Years Clinical Whole-Exome Sequencing: Lessons Learned From the First Two Years Communication with the ordering clinician is essential Diagnostic yield is better than expected Trio cases are much easier and more fruitful than singletons Generic autism and developmental delay don t yield much Test volume keeps growing Insurers are more open to coverage than anticipated Communication with the ordering clinician is essential Diagnostic yield is better than expected Trio cases are much easier and more fruitful than singletons Generic autism and developmental delay don t yield much Test volume keeps growing Insurers are more open to coverage than anticipated

5 Will whole-genome sequencing replace single-gene or gene-panel testing? Case #2 1-year-old male Developmental delay Seizures Microcephaly Parental consanguinity Case #2 Results Homozygous missense variant in CLN8 gene: Pro229Ala Located within an extensive region of homozygosity Known mutation causing neuronal ceroid lipofuscinosis (Batten disease) Case #2 Results - 2 Homozygous missense variant in CLN8 gene: Pro229Ala Located within an extensive region of homozygosity Known mutation causing neuronal ceroid lipofuscinosis (Batten disease) Incidental finding: Homozygous nonsense variant in APP gene