Genetic Screening, Genetic Counseling, Prenatal Testing

1. Genetic Counseling
Screening and
Prenatal Testing
M.Phil
17-2-15

2. Learning Objectives
• By the end of this lecture……….we all should
be able to appreciate:
– The need and purpose of Genetic Screening
– The methodology of Genetic Counseling
– Need and application of Genetic Counseling
– Prenatal Testing

3. How Do Genes Influence Who We Are?
Phenotype: Predisposition to
superior athletic
ability
Predisposition to
breast cancer
Predisposition to
sociopathic
behavior

4. Case Report
A man with cataracts, temporal balding, wasting
of his facial muscles and a myotonic grip
presents along with his young adult daughter,
who had similar features. What would you do
for the patient?

5. Genetic Evaluation
Data gathering
History, especially family history
Physical examination - major and subtle findings
Pattern recognition
Laboratory testing – EMG, DNA

6. A Family with Multiple Cases of
Myotonic Dystrophy
cataracts
Temporal balding
Cataracts
Hoarseness
Myotonia
Daytime somnolence
Weakness
Balding
Cardiac arrhythmia

7. Physical Diagnosis of Myotonic Dystrophy
Grip release test
Facial features

8. EMG Testing for Myotonic Dystrophy

9. Newborn Screening: WHY ?
• Detect an affected
infant before before
symptoms to prevent or
reduce morbidity and
mortality
• Provide parents and
family reproductive
options for future
pregnancies

10. Fetal Nuchal Translucency Measurement Improves
Detection Rate for Chromosomal Abnormalities
GA: 11 wks, 3 days to 13 wks, 6 days
Crown-rump length: 45 to 84mm
Increased in chromosomal disorders,
congenital heart disease
congenital infection
fetal hydrops
rare genetic disease
(Noonan syndrome,
lethal multiple pterigium,
AR cystic hygroma)

11. Interphase Amniotic Fluid FISH Analysis
for Chromosomal Aneuplodies
Protocol
2-4 ml clear amniotic fluid
Centrifuged, fixed and dropped on slide
Hybridized with chr 13, 18, 21, X, Y probes
Count at least 50 cells
>85% aneuploid  abnormal
>85% euploid  normal
Others  indeterminate

12. Chromosome Variation
• Karyotype
• 23 pairs autosomes, 2 sex
chromosomes
• Each chromosome has a
characteristic banding pattern
• What is the most common
genetic variation you see in
karyotypes from a normal
population?
46, XX versus 46, XY

13. When to order cytogenetic testing
Multiple congenital anomalies
Mental retardation of unknown origin or associated with minor or major malformations
Multiple unexplained spontaneous abortions
Ambiguous genitalia
Prenatal testing
Abnormal prenatal screen
Ultrasound abnormalities

14. Genetic Counseling

15. Adults who might seek genetic services:
• Those with reproductive problems
• Those with a known genetic disorder in the
family
• Those with symptoms of a genetic disorder
• Those with family history of cancer

16. Case Study
• At the time of her annual physical, your
patient, a 30-year old woman, asks about the
“breast cancer gene”. She is Jewish and has
been reading in the paper that Jewish women
may be more likely to have this “gene”. She
has two older sisters, aged 33 and 35, who are
also worried about their risks.

17. Genetic testing for BRCA1/2
• All testing in North America performed by a single lab, Myriad
• Exons and adjacent regions sequenced. Also look for large duplications and
deletions. Mutation-specific testing is also available.
• Possible results:
– Mutation positive
– Mutation negative (known mutation in family)
– Variant of unknown significance (This happens ~10% of the time)
– No mutation found
• Preferable procedure is to do test on an affected family member first

18. Mendelian versus complex traits
• Mendelian traits
– Are determined by the independent action of a single major gene
– Mutation in this gene is necessary and sufficient for phenotype
– Have predictable inheritance patterns
Cystic fibrosis
Risk to each sib is 25% and we can do prenatal testing

19. Mendelian versus complex traits
• Complex traits
– Exhibit familial clustering but not predictable
inheritance patterns
Cleft palate
Recurrence risk is 3% (compared to population risk of 0.1%)

20. Benefits to determining genetic
factors that influence a complex trait
– Provide a molecular definition of the trait
– Improve understanding of disease etiology and mechanism
– Can offer early risk assessment
– Aids in discovery of new, targeted drugs
– Can be utilized for disease prevention

21. PENETRANCE & EXPRESSIVITY
EXPRESSIVITY, the degree to which a
particular gene exhibits itself in the
phenotype of an organism, once it has
undergone penetrance.
e.g., a penetrant baldness gene in man
can have a wide range of expressivity,
from thinning hair to complete lack of hair.

22. PENETRANCE & EXPRESSIVITY
PENETRANCE, the percentage of individuals
with a particular genotype that display the
genotype in the phenotype.
e.g., a dominant gene for baldness is 100%
dominant in males and 0% penetrant in most
females, because the gene requires high levels
of the male hormone for expression.
Once a gene shows penetrance it may show a
range of expressivity of phenotype.

23. Principles of Screening
• What makes a test a screening test?
– Diagnostic test used to establish diagnosis
– Screening test used to distinguish those who
PROBABLY have the disorder from those who
probably DON’T have the disorder
– A “POSITIVE” screening test must be followed up
by a definitive diagnostic test!
– It’s not the test, it’s how you use it…

24. Screening
Family Screening:
• Screening of individuals and couples known to be at significant or
high risk because of a positive family history - sometimes referred
to as targeted, or family, screening because it focuses on those
most likely to benefit.
– Carrier
– Heterozygote screening.
– Pre-symptomatic testing.
General screening
• Low risk population.
• Primary objective is to enhance autonomy by enabling individuals
to be better informed about genetic risks and reproductive options.
• Secondary goal is the prevention of morbidity due to genetic
disease and alleviation of the suffering that this would impose.

25. Is genetic screening the only choice?
• In some autosomal recessive disorders (Tay-Sachs
disease, sickle-cell disease) carriers can be recognized
with a high degree of certainty using biochemical or
hematological techniques without DNA analysis.
• In other single-gene disorders, it is possible to detect
or confirm carrier status by biochemical means in only
a proportion of carriers,
– The presence of abnormal coagulation study results in a
woman at risk of being a carrier for hemophilia. A
significant proportion carriers of hemophilia will have
normal coagulation, so that a normal result in a woman at
risk does not exclude her from being a carrier.

26. An Example: Career Testing in
Orthodox Jews
• Carrier testing for Tay-Sachs disease in many orthodox Jewish communities.
• Due to faith-based objections to termination of pregnancy, carrier testing may
actually be crucial in the selection of life partners in these communities.
• For a couple considering betrothal, or engagement to be married, they first see
their rabbi.
• In addition to listening to his spiritual advice, they will both undergo carrier testing
for Tay-Sachs disease.
• If both prove to be carriers the proposed engagement will be called off, leaving
them free to look for a new partner.
• If only one proves to be a carrier the engagement can proceed, although the rabbi
does not disclose which one is the carrier.
• While such a strategy to prevent genetic disease may be possible in many
communities where inbreeding is the norm, and their 'private' diseases have been
well characterized either biochemically or by molecular genetics.
• In practice this is very rare.

27. “The Square”
A
True
Positive
B
False
Positive
C
False
Negative
D
True
Negative
Sensitivity = A/(A+C)
[TP/all those with disease]
Specificity = D/(B+D)
[TN/all those without disease]
PPV = A/(A+B)
[TP/all positives]
NPV = D/(C+D)
[TN/all negatives]

28. Genetic counseling
• When do we need Genetic counseling?
• A consultand?

29. The role of Genetic Counselor?

30. Purpose of Genetic counseling
• The medical diagnosis and its implications in
terms of prognosis and possible treatment
• The mode of inheritance of the disorder and
the risk of developing and/ or transmitting it
• The choices or options available for dealing
with the risks.

31. Establishing a Diagnosis

32. Haemophilia

33. Genetic heterogeneity

34. Problems in Genetic Counseling
• Consanguinity

35. Thank you