Chromosomal Abnormalities Flashcards
What is cytogenetics?
Cytogenetics is the study of the genetic constitution of cells though the visualisation and analysis of chromosomes.
Why do cytogenetic analysis?
To get an accurate diagnosis/ prognosis of clinical problems.
- Identify the syndrome associated with the particular abnormality
- Account for the phenotype
- Account for pregnancy loss
Better clinical management
-eg Hormone treatment for Klinefelter syndrome (boys with XXY)
Assess future reproductive risks
- Risk of live born abnormal child
- of if Previous Down syndrome pregnancy then there is a 1% increase above the level normal in the population that you will have another
Prenatal diagnosis
-TOP of affected pregnancy / planning for management at birth
Why would somebody undergo cytogenetic testing?
To look for constitutional abnormalities (chromosomal abnormalities from birth) eg:
- Prenatal diagnosis
- Birth defects
- Abnormal Sexual Development
- Infertility
- Recurrent foetal loss
Or to look for acquired abnormalities eg
- Leukemias (acute disease AML ALL, chronic diseases CML, myelodysplasia / myeloproliferative disorders)
- Solid tumours
- Specific translocation / abnormalities can give prognostic information.
What are the two different methods of prenatal diagnosis?
Chronic Villus Sampling - This is done at the end of the first trimester (11-12 weeks) and there is a 1.2% risk of miscarriage.
Amniocentesis - this is done from 15 weeks onwards (this is when there is sufficient amniotic fluid to take) and there is a 0.8% risk of miscarriage.
Why do people undergo prenatal screening?
Maternal serum screening for Down syndrome - use certain biochemical markers and things like age and if risk is larger than 1:150 then they are offered a prenatal diagnosis. This is done in the first trimester.
If family know they have abnormal chromosomes and there is a risk to the child - offer reassurance.
If an abnormal ultrasound scan is seen - eg cystic hygroma, cleft palate or lip, heart abnormality, limb abnormalities.
DNA studies - eg for cystic fibrosis
What ways are there to undergo cytogenetic testing?
Karyotyping - for chromosomal analysis
FISH (fluorescent in situ hybridisation) - allows for analysis of specific regions on chromosomes as probes use specific loci.
Microarray comparative genomic hybridisation (aCGH)
What is Karyotyping?
Karyotyping is systematic sorting of chromosomes. It screens the whole genome but, it is comparatively a low resolution. The metaphase chromosomes are stained, paired up and grouped together and any abnormalities found are described using the standard nomenclature.
How is chromosome analysis done?
The number of chromosomes present is counted
Each chromosome pair is identified
They are then assessed to see if there is any extra or missing material and if all the bands are in the right place
All the pairs must be seen at the correct resolution twice
Then, all chromosomes are independently rechecked another time (chromosomes will have been checked 3 times in total).
What is standard nomenclature for reporting chromosomal abnormalities?
Use chromosome number, sex compliment and structural changes separates by commas. Eg 46,XY is a normal female and 47,XY+21 is a female with trisomy 21 (Down syndrome). There are NO SPACES in the Karyotype.
What is aneuploidy? What types of aneuploidy are there?
Aneuploidy is the loss or gain of whole chromosomes. It arises due to an error in cell division in meiosis. You can get trisomies (eg Down’s syndrome +21, Patau syndrome +13, Edwards syndrome +18) or monosomies (Turners syndrome in which female only has one X is the only full monosomy which is viable. This is due to X inactivation) or polyploidy.
What is polyploidy? What is it’s most common cause?
Polyploidy is a gain of a whole haploid set of chromosomes. This causes triploidy (3n).
The most common cause of polyploidy is polyspermy. This is the fertilisation of an egg by more than one sperm.
Triploidy occurs in 2-3% of all pregnancies and in around 15% of all miscarriages. Term deliveries die shortly after birth.
What causes aneuploidy?
Aneuploidy is caused by chromosome nondisjunction at one of the mitotic cell divisions. This forms gametes with a missing chromosome and an extra chromosome. Which chromosome is missing / extra influences viability (only +21 is viable for a full lifespan and +13 and +18 at all). If this occurs during mitotic cell division it can cause mosaicism (two cell populations in an individual).
What are symptoms of Down’s syndrome?
Hypotonia (low muscle tone / reduced muscle strength) Characteristic facial features Intellectual disability Heart defects Increased prevalence of Leukaemia Increased incidence of early Alzheimer’s
What is Edwards Syndrome?
This is trisomy 18. It is characterised by: Small lower jaw, Prominent occiput (back of head) Low-set ears Rocker bottom feet Overlapping fingers
It has an incidence of 1:6000 and is more common in women. It is caused by a maternal meiosis II error and the modal lifespan is 5-15 days, although nearly all diagnoses are made prenatally.
What is patau syndrome?
This is caused by trisomy 13.
It involved multiple congenital abnormalities such as polydactyl and holoprosensephaly. It has an incidence of 1:12000 and the majority die in the prenatal period.
