Clinical genetics Flashcards
how can errors happen in meiosis and dna replication
DNA replication:
-new mutations (copying errors)
Meiotic cell division:
-anomalies of chromosome number (non-disjunction)
-anomalies of chromosome structure (unequal crossing-over)
gamete containng the genetic anomaly
resulting from an error in zygote
What are the main classes of genetic disorders
Mutations in single genes
Common complex/
Multifactorial diseases
Chromosome imbalance
causes change in gene dosage (too much or too little geentic material)
What are the most common chromome abnormlaity
numerical
-too many, little extra or mssing
structural
different cell lines
common chromsome numerical abnormalities
Autosomes
Down syndrome (trisomy 21: 47,XX,+21)
Edwards syndrome (trisomy 18: 47,XX,+18)
Patau syndrome (trisomy 13: 47,XX+13)
**Sex chromosomes
**Turner syndrome 45,X
Klinefelter syndrome 47,XXY
**All chromosomes
**Triploidy (69 chromosomes
any other trisomy may be too large to carry to term
genetic content of sex chromsomes is less, so aneploudity less severe
What do genes do
code for functional protein
mutation: can make no protein, protein that doesnt work
How to we know if a pregnancy has an increased risk of genetic condition
we do testing and ask questions
-genetic diagnosis in rekative
-there is a pattern of genetic conditions in pregnancy
-can see in pregnancy scans there is a genetic risk
-can look at results of genetic testing in pregnancy
take family history first, and draw up the pedigree
What can we find out from doing a pedigree
- Family history of genetic disorder
- Parental consanguinity (marriage between two people who are related as second cousins or closer)
- Population ancestry
- increased maternal age
- increased paternal age
- Environmental exposure affecting DNA
How is cystic fibrosis inherited
autosomal reccessive
25% chance
population carrier test is 1/23 for CF
what can increase risk of having a genetic condition
Consanguineous
people who are closley releated more time carrier same reccesive gene
Roberstonian transolcation and reciporcal difference
-end to end fusion of specfic chromsomes (13,14,15,21,22)
reciprocal; any non paired chrosmome fusing
1/500
reciporcal translocation: as long as all chrosmome material is there when it swicthed around we show no phenotype
but… having a balanced translocation puts you at risk at congential anomlies -> risk of miscarriages
What happens when reicproal translocation carrier has a gamete
- person could put normal chromsomes in gamete together
- they may put one normal chromsome with a translocation chromsome ( can have a partial trisomy or monosmy)
- if theres two translocated chromsome -> zygote is a balanced chroamome -> risk passing it to next gen
big genetic imbalance can lead to Miscarriage,
congenital malformation,
developmental delay,
intellectual disability
How can elevated maternal age affect genetic disorders
-may led to non dysjunction
-spindle fibres go through wear and tear
-so chrosmomes may not cleanly seperate from each other
- get two in one egg and the other has nothing
- trisomy 21 happens like tgis
monosomy is lethal
How can paternal age increase risk of genetic disorder
-can have de novo or new muataion as a result of increase paternal age
-older a mans sperm, it goes through more cell divisions, more cell divisions means more chance of mutations
Why make a genetic diagnosis in pregnancy
-for infomation -> can alter management (may need treatment)
-could provide option for termination if condition is severe
If a couple has an increased risk what are their options
-may choose no pregancies (donor gametes, adoption)
-screening :via genetic testing -> (invasive), targetted genetic testing (non invasive-> looking at maternal blood sample)
-pre-implanation genetic diagnosis (PGD)
Pregnancy scans
what are the uses of genetics
i Detects structural abnormalities
* Routine screening of low risk pregnancies
– 12 weeks dating scan (check viablity and check heart beat, may pick up major sturctual ones but not much)
– 20 weeks structural anomoly scan
if anything is picked up at 20 week scan -can do high resolution scanning for specific disorder (e.g cardiac/Fetal MRI)
if we know theres genetic test, can get babies DNA to check for sure
Safe and non invasive
Diagnostic limitations: may not pick up certain conditions such as neurodevelopment, unless theres leison can’t pick up on scan
What is CVS
-From 11 weeks gestation
* Under ultrasound guidance
-small needle through tummy, get soem chronious villus to get some of babies DNA, and then do
* Chromosome analysis- to look for specfic gene sequence
* Miscarriage rate ~ 1-%
* Associated with limb reduction defects if performed before 9 weeeks
* DNA analysis- uncultured cells- results 1-2 weeks
What happens during amniocentesis
-15 weeks gesation
-take sample from aminiotic fluid, can obtain from babies DNA
-can then find cells, and culture cells
-takes 2-3 weeks to get result
-Miscarriage rate ~ 0.5-1%
if risk known have CVS, AC happens if risk was not really known
What is pre natal genetic testing
-Blood test from the mother to diagnose a genetic condition in the fetus
-relies on fetal cells are circulating in maternal blood (happens around 8-9 weeks)
-look at markers to look at what cells are from mum and baby
-can do genetic tests for fetal sexing (can check whether x or y chromsomes are circulating in mums blood -> important for x linked condition)
-can do NIPT (for trisomy 13,18,21 -> inaccurate + and combine with nuchal test)
-can do NIPD
Happens earlier in pregnancy
No risk of miscarriage
NIPT- screening not diagnostic test
Not available for all conditions
What is pre-implanation diagnosis
-testing embroyo before it is placed in uterus
-IVF
-stimulate lots of eggs
-get sperm
-make embroyo
-blastomere biopsosy is taken
-genetic test on that one cell
-if it shows embroyo does not have genetic condition, then reimplant embryo
-hope you get a pregnancy
wants to be embroyo free of genetic condition into uterus
uses ivf, and highly specalised, HEFA decides what conditions can be granted this service
What happens if your a low risk pregancy and they pick smth up at 20 week scan
-may be highly suggestive pregnancy has genetic condition
-need to rule out chromosomal abnormalities if there is a structual abnormality (can count chromsomes in aminocentisis)
-can do micro-array (to see if theres chrosmoem mateial missing or extra)
-look if its single gene disoder (using rapid exome testing)
exome: coding bits of genetic material -> test baby mum and dad exomes
