Clinical genetics

Question 1

how can errors happen in meiosis and dna replication

Answer 1

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

Question 2

What are the main classes of genetic disorders

Answer 2

Mutations in single genes
Common complex/
Multifactorial diseases
Chromosome imbalance
causes change in gene dosage (too much or too little geentic material)

Question 3

What are the most common chromome abnormlaity

Answer 3

numerical
-too many, little extra or mssing

structural

different cell lines

Question 4

common chromsome numerical abnormalities

Answer 4

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

Question 5

What do genes do

Answer 5

code for functional protein

mutation: can make no protein, protein that doesnt work

Question 6

How to we know if a pregnancy has an increased risk of genetic condition

Answer 6

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

Question 7

What can we find out from doing a pedigree

Answer 7

• 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

Question 8

How is cystic fibrosis inherited

Answer 8

autosomal reccessive

25% chance

population carrier test is 1/23 for CF

Question 9

what can increase risk of having a genetic condition

Answer 9

Consanguineous

people who are closley releated more time carrier same reccesive gene

Question 10

Roberstonian transolcation and reciporcal difference

Answer 10

-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

Question 11

What happens when reicproal translocation carrier has a gamete

Answer 11

1. person could put normal chromsomes in gamete together
2. they may put one normal chromsome with a translocation chromsome ( can have a partial trisomy or monosmy)
3. 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

Question 12

How can elevated maternal age affect genetic disorders

Answer 12

-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

Question 13

How can paternal age increase risk of genetic disorder

Answer 13

-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

Question 14

Why make a genetic diagnosis in pregnancy

Answer 14

-for infomation -> can alter management (may need treatment)
-could provide option for termination if condition is severe

Question 15

If a couple has an increased risk what are their options

Answer 15

-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)

Question 16

Pregnancy scans

what are the uses of genetics

Answer 16

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

Question 17

What is CVS

Answer 17

-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

Question 18

What happens during amniocentesis

Answer 18

-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

Question 19

What is pre natal genetic testing

Answer 19

-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

Question 20

What is pre-implanation diagnosis

Answer 20

-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

Question 21

What happens if your a low risk pregancy and they pick smth up at 20 week scan

Answer 21

-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