1. A Primer on Genetic Testing:
What Is It? How Does It Work? Why Does It Matter?
www.LabResultsForLife.com

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

3. 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

4. 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

5. 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

6. Genetic Tests for Constitutional Mutations
• Molecular Tests
• Cytogenetic Tests
• Biochemical Tests

7. 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

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

9. 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

10. 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

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

12. 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

13. 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

14. 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

15. 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

16. 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)

17. 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

18. 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

19. 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

20. 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

21. 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.

22. 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

23. 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

24. 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