Lecture 5: Mutations and Disease Gene testing Flashcards
List some resons for a referral to a genetics clinic
- A child is born with several abnormalities
- There is a history in the family of a medical condition
- Women who have a history of several miscarriages
- Women over 35 years and pregnant
- A family member diagnosed with cancer at a young age
- Family history of cancer
- Anyone uncertain about their genetic risks and family medical
background.
what is diagnostic testing used for
Used to help confirm a condition in a patient who already has
symptoms.
what is Pre-symptomatic or predictive testing used for
Offered to asymptomatic individuals with an increased risk of a family history of a genetic disorder.
Important if early diagnosis allows interventions which improve health outcomes.
at what three stages can genetics be tested in an embryo?
- pre-implantation genetic diagnosis
- pre-natal diagnosis (scanning fetus)
- pre-symptomatic genetic testing
What are some practical issues of genetic testing
- Have we got a confirmed phenotype?
- What is the pattern of inheritance?
- Which genes should we test, is the test available?
- What is the advice to the patient if the test is positive or negative?
- Issues to consider:
- genetic heterogeneity (different genetic mechanisms that produce the same or similar phenotypes)
- non-penetrance (individual has a trait-associated or disease-causing genetic variant, but the individual does not have the phenotype or condition.)
- expressivity
- (non-paternity)
what is prenatal diagnosis
Chromosomal and genetic analysis of a fetus can be
determined by analysis of cultured cells from the amniotic fluid
why was prenatal diagnosis important
for testing women of late maternal age or an increased risk of Down syndrome (trisomy 21)
what are some implications of prenatal diagnosis
ethical issues surrounding prenatal diagnosis and
selective termination of pregnancy are both complex and
emotive
at what maternal age does incidence of Down syndrome increase
35
what are the goals of prenatal diagnosis
- Not simply to detect abnormalities and terminate pregnancy
- Allow parents to make an informed choice
- Provide reassurance and reduce anxiety in high risk groups, who might otherwise forego pregnancy
- To provide couples with an affected child time to prepare for the arrival
- To enable prenatal treatment of the affected child
what are some methods of prenatal diagnosis in down syndrome
non-invasive testing
- Maternal serum alpha-fetoprotein (AFP)
- Maternal serum screen (AFP, inhibin A, hCG, oestriol)
- Ultrasonography
what are some general methods of prenatal diagnosis
invasive testing
- amniocentesis
- chorionic villus sampling
both invasive associated with small risk of fetal loss
Explain how amniocentesis works
- Amniotic fluid (~20mL) is collected for
chromosome studies, enzyme
measurements (AFP for neural tube
defects) or DNA studies, in combination
with ultrasound - The amniotic cells contain fetal cells
that need to be cultured - Usually performed at the 14-16th week,
but can be performed as early as 10
weeks - Associated with ~0.5-1% risk of inducing miscarriage over the baseline risk of 2- 3% of any pregnancy at this stage of
gestation
explain how chorionic villus sampling works
- Involves biopsy of tissue from the villous area of the chorion transcervically
or transabdominally usually ~10-14 weeks, in combination with ultrasound - Advantage of CVS is getting results at an earlier stage, and allow for an
earlier termination - However, no AFP testing
- Increase in fetal loss is ~1% compared to baseline of 2-5% at this time of
gestation
what are some general non-invasive prenatal testing methods
- use fetal DNA in maternal plasma to then sequence, analyse fetal DNA signal and determine personalized risk score
what is PGD and what is it used for
- Pre-implantation Genetic Diagnosis
- PGD is the use of in vitro fertilisation (IVF) and genetic testing to select embryos free of a specific genetic condition for transfer to the uterus
- Offered as an alternative to pregnancy termination
- Molecular analysis can be undertaken by PCR and
cytogenetic analysis by FISH, SNP arrays, array CGH - An unaffected embryo is transferred to the uterus of
the mother - Affected embryos are discarded, raising ethical issues
- What should we test for? Specific mutations OR
‘Everything’?
What happens if a mutation is found in PGD
Once a mutation in a gene has been found, need to prove that thatmutation is actually involved in causing the disease (a ‘driver’) rather than being a ‘passenger mutation’.
use mutation screening
Sample 100 individuals and you screen your patient and they have the same mutation - likely driver
Only in affected vs unaffectd- increaes likelihood a driver mutation
need to do Functional testing, experiment in lab, find out functional consequence of mutation
see how it affects the protein – key info on how important mutation is
what are some treatments for mutation carriers
- The gene test outcome for an individual patient or family member should lead to more informed and directed recommendations for preventative
interventions. - Persons at risk of an inherited disease can be screened for associated features of the disease
- May lead to:
change in lifestyle
drug treatment
prophylactic surgery
why do genetic tests have ethical issues
Implication for family - may reveal infomration or disease risk of family members
Genetic test – stays with you for life
Permanent record about you and family member – has implications
Highly accurate - don’t want errors in these, robust and specific labs
Accurate translation of information, genetic counselor – pentrance
Test can vary in their sensitivity false positives for example
why is seeing a gentic counsellor important in genetic testing
Increase the family’s understanding about a genetic disease(s), the risks and benefits of genetic testing and disease management, and available options.
