BMS2042 Lecture Notes - Lecture 19: Chloroplast, Melas Syndrome, Intron
30 May 2018
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Week 7. Diagnostic genetic testing, Non-Mendelian
inheritance, and Mitochondrial DNA disorders
DIAGNOSTIC GENETIC TESTING
• Prenatal diagnosis:
o Aims to inform couples about risk of birth defects or genetic disorders and how to
manage this risk
o Takes place when:
Family history
Been tested as carrier
Increasing maternal age
Routine screening
o Test may provide:
Choice to terminate pregnancy if child has severe genetic disorder
Reassurance that child is healthy
Better planning for prenatal care
Psychological preparation
o Suggested for:
Mother of advanced age
If previous child has chromosomal abnormality
If parents have chromosomal abnormality
Family history
Risk of neural tube disorder (found in ultrasound, first 2 months of pregnancy)
Abnormal results from ultrasound
• Non-invasive vs invasive diagnostic testing:
Non-invasive prenatal diagnostic testing
Invasive prenatal diagnostic testing
• Test for sporadic Neural Tube defects
(NTDs)
o 95% infants are born into families
with no known history
o Associated with high levels of alpha-
fetoprotein -> produced in foetal
liver and excreted into amniotic fluid
and absorbed into mothers
circulation via placenta and can be
detected in maternal serum
(MSAFP) – non-invasive
immunoassay and not 100%
accurate
• Maternal serum protein tests:
eg. pregnancy associated plasma protein A
(PAPP-A) decreased in 1st trimester for all
three common trisomies
• Have some risk of miscarriage, only used for
high risk pregnancy eg. family history
• Amniocentesis:
o Needle is inserted into amniotic sac
o No anaesthesia
o Amniotic fluid is sampled (contains
foetal cells which can be tested)
o Can also do biochemical analysis of
amniotic fluid to detect proteins eg.
alpha-fetoprotein
o >15 weeks
• Chorionic villus sampling (CVS):
o Needle through cervix or abdomen
o Biopsy of tissue from the villous area
of the chorion (part of placenta that
derives from embryonic tissue)
o Performed between 10th and 12th
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eg. triple screen for further 3 proteins
• Ultrasound: nuchal translucency (thickening
at back of neck, abnormal fluid build-up ->
Down syndrome)
week
o Preferred technique before week 15
o Can be complicated by mosaicism
• Cytogenesis: carried out on cells from
amniocentesis or CVS (foetal cell ->
fibroblast: skin cells)
o Karyotyping using G banded
metaphase spreads
o FISH to check numbers of
chromosomes
o If abnormality like translocations,
parents will also be checked to see
whether it was inherited
• Sreeig for trisoies suh as Do’s sydroe:
o Women of advanced age are offered amniocentesis or CVS
o Despite increased risk of abnormalities with increased maternal age, 70% of all children
with trisomies are born to women <35
-> invasive testing is not usually offered or recommended for these women
• Risk figures for Dow’s sydroe:
o 1st trimester screening
o Maternal age + nuchal translucency : 63% detection rate with 5% false-positive
o Add maternal serum free beta HCG subunit and PAP-A: 80% detection rate with 5%
false-positive
o Add past trisomy 21 pregnancy: recurrence risk increases ~1%
• DNA testing:
o To test for inheritance for specific mutations
eg. allele-specific oligonucleotide detection, RFLP
o Problems:
Not all genetic diseases have a known gene
Specific gene causing disease must be known
Specific allele must be known
Variable expressivity
Variable penetrance
Mitochondrial disorders hard to predict because of heteroplasmy
• Genetic testing:
o Population based method of identifying individuals with increased susceptibility or risk
for a genetic disease
o Testing everyone in population
-> in order to produce improved outcome for individuals identified
o Relies on:
Clinical validity: screening test is valid if it is predictive for disease
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find more resources at oneclass.com
Clinical utility: screening is useful if medical care of the individual can be
changed based on test results and therefore improve the outcome of care
• Screening for heterozygotes
o In populations with high frequency of carriers
o If inexpensive and dependable test that is specific and sensitive
o If offers genetic counselling
o Prenatal diagnosis
o If acceptance and voluntary participation by population targeted for screening
o Eg. Tay-Sachs disease in jewish populations -> carried out through Jewish high schools in
Australia
o Issues with privacy, is it voluntary?, have all causative alleles been identified? Can they
all be screened?
find more resources at oneclass.com
find more resources at oneclass.com
