What is Genetic Testing? And what is its value?

Sherri J. Bale, Ph.D., FACMG President and Clinical Director GeneDx

Definition of Genetic Testing:

The analysis of human DNA in any of its forms or related products (chromosomes, RNA, proteins)

Uses of Genetic Testing:

To detect disease-related genotypes, mutations, phenotypes, or karyotypes for clinical purposes

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

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

Genetic Tests for Constitutional Mutations

Molecular Tests Cytogenetic Tests Biochemical Tests

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

Molecular Test: Muscular Dystrophy

Obtain blood sample from child Read the DNA sequence of the DMD gene Identify the mutation that caused the disease

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 Moms next pregnancy OR Can offer pre-implantation genetic diagnosis Can provide information about prognosis

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

Cytogenetic Test: Child with MCA and autism

Obtain a blood sample from baby Look at chromosomes

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

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

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

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 babys blood

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)

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

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

How is this information useful?

Patients whos 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

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

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.

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

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

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