1. What is Genetic Testing? And what is its value? Sherri J. Bale, Ph.D., FACMG President and Clinical Director GeneDx

2. Definition of Genetic Testing: The analysis of human DNA in any of its forms or related products (chromosomes, RNA, proteins) To detect disease-related genotypes, mutations, phenotypes, or karyotypes for clinical purposes Uses of Genetic Testing:

3. More definitions Genotype vs. Phenotype –The genetic make-up, as distinguished from the physical appearance Mutation –A genetic change, usually one that is associated with a disease Karyotype –A visual presentation of chromosomes

4. Two Main Types of Genetic Tests Constitutional –Tests for mutations that affect ALL CELLS in the body, and have been there since conception Acquired –Tests for changes that affect only certain cells or cell types in the body, and that occurred later in life

5. Genetic Tests for Constitutional Mutations Molecular Tests Cytogenetic Tests Biochemical Tests

6. Molecular Test: Example Analysis of DNA sequence in patient with a rare inherited disease –Muscular Dystrophy –Gene: DMD –Clinical Picture 1 in 3500 male births progressive muscle weakness starting in early childhood wheelchair by age 12 death in 20s

7. Molecular Test: Muscular Dystrophy Obtain blood sample from child Read the DNA sequence of the DMD gene Identify the mutation that caused the disease

8. How is this information useful? Can test Mom – Is she an unaffected carrier of the mutation? Is she at risk to have more children with this disease? Can test siblings of affected child Can offer prenatal diagnosis in Mom’s next pregnancy OR Can offer pre-implantation genetic diagnosis Can provide information about prognosis

9. Cytogenetic Test: Example Karyotype – to examine the chromosomal complement of an individual including number, form, and size of the chromosomes. Frequently used for children who present with multiple anomalies, developmental delay, autism

10. Cytogenetic Test: Child with MCA and autism Obtain a blood sample from baby Look at chromosomes

11. New type of Cytogenetic Test Cross between a molecular and Cytogenetic test – arrayCGH- tests for presence/absence of genes at 1000s of positions on each chromosome. Much more sensitive than a karyotype

12. How is this information useful? Can determine exactly which genes are involved Can test parents and siblings of affected child to see if they carry the abnormality Can offer prenatal diagnosis in next pregnancy OR Can offer pre-implantation genetic diagnosis Can provide information about prognosis

13. Biochemical Test Analyzes the quantity of a downstream product of a gene (e.g. not looking directly at the gene, or the chromosome). Example: Newborn Screening –Mandated in all 50 states –Twenty primary targets that all states do –Over 4 million newborns tested each year

14. Biochemical Test: PKU Phenylketonuria –Inherited metabolic disorder –If untreated, leads to mental retardation, seizures –Affects 1 in 20,000 newborns Missing enzyme: Phenylalanine Hydroxylase Measure amount of Phenylalanine in baby’s blood

15. How is this information useful? Can diagnose the baby in time to treat and avoid all clinical consequences of the disease Treatment: Restrict phenylalanine in the diet Can test siblings of affected child to see if they are carriers for the disease (1 in 70 in the general population are carriers)

16. Genetic Tests for Acquired Mutations Molecular Tests Cytogenetic Tests Tests for changes that affect only certain cells or cell types in the body, and that occurred later in life

17. Molecular Test for Acquired Disease KRAS gene test on tumor tissue from patients with colorectal cancer –Obtain tumor from patient –Extract DNA; treat with enzyme that allows visualization of the mutation

18. How is this information useful? Patients who’s colon tumors do not have a KRAS mutation are much more likely to respond to Cetuximab therapy Identifies patients most likely to benefit from specific therapies Allows choice of alternative therapies (and saves time and money) for patients unlikely to respond

19. Cytogenetic Test for Acquired Disease: Example Her-2/neu gene amplification in Breast Cancer –Occurs early in oncogenesis –Seen in up to 1/3 of breast cancers –Associated with poor prognosis –Responds to Herceptin (trastuzumab) treatment –Does not respond to Tamoxifen treatment

20. Cytogenetic Test for Acquired Disease FISH (Fluorescent In Situ Hybridization) for HER-2/neu is a gene-based test that allows one to count the number of HER-2 genes in a cell.

21. How is this information useful? Assists in selection of patients for chemotherapy, and which therapy to use Predicts response to adjuvant therapy Increases survival Allows choice of alternative therapies (and saves time and money) for patients unlikely to respond

22. Genetic Testing in the News Today Recreational Genetics –23andMe, KnowMe, Navigenics Nutrigenomics –Sciona, Genelex, Market America, Suracell Ancestry Testing –African Ancestry,GeneTree,DNAPrint Skin and Hair Care –HairDx, Dermagenetics Canine Breed Analysis Ready for clinical use Not ready for prime time

23. Summary Constitutional genetic tests impact patients with inherited disorders and their families, by providing information about diagnosis, prognosis, treatment, and informing reproductive decisions Genetic tests for acquired diseases impact patients with diseases like cancer, provide information about diagnosis and prognosis, and inform treatment decisions Genetics and genetic testing impacts many phases of our lives, and will do so even more in the future