genetic screening counseling prenatal testing m phil 17 2-15

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

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Genetic Counseling Screening and

Prenatal TestingM.Phil

17-2-15

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

How Do Genes Influence Who We Are?

Phenotype: Predisposition to superior athleticability

Predisposition to breast cancer

Predisposition tosociopathicbehavior

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?

Genetic EvaluationData gathering

History, especially family history

Physical examination - major and subtle findings

Pattern recognition

Laboratory testing – EMG, DNA

A Family with Multiple Cases of Myotonic Dystrophy

cataracts

Temporal baldingCataractsHoarsenessMyotoniaDaytime somnolence

Weakness Balding Cardiac arrhythmia

Physical Diagnosis of Myotonic Dystrophy

Grip release test

Facial features

EMG Testing for Myotonic Dystrophy

Newborn Screening: WHY ?

• Detect an affected infant before beforesymptoms to prevent or reduce morbidity and mortality

• Provide parents and family reproductive options for future pregnancies

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 infectionfetal hydropsrare genetic disease (Noonan syndrome, lethal multiple pterigium, AR cystic hygroma)

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

When to order cytogenetic testingMultiple congenital anomalies

Mental retardation of unknown origin or associated with minor or major malformations

Multiple unexplained spontaneous abortions

Ambiguous genitalia

Prenatal testingAbnormal prenatal screen

Ultrasound abnormalities

Genetic Counseling

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

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.

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

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

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%)

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

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.

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.

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…

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.

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.

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.

“The Square”

ATrue Positive

BFalse Positive

CFalse Negative

DTrue 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]

Genetic counseling

• When do we need Genetic counseling?

• A consultand?

The role of Genetic Counselor?

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.

Establishing a Diagnosis

Haemophilia

Genetic heterogeneity

Problems in Genetic Counseling

• Consanguinity

Thank you