5. Chromosomal Pathology Flashcards
In what percentage of live births are chromosome abnormalities found
0.7%
What percent of stillbirths are chromosome abnormalities found in
5%
What percent of pregnancy losses are chromosomal abnormalities found in
50%
What is dosage effect
Number of copies variation = CNV
Loss is usually worse than gain
What can deletion of one chromosomal homologue result in
Unmasking of a recessive disorder
Diploidy meaning
Normal state of chromosome number
Anuploidy meaning
1 or more extra or missing chromosomes eg, trisomy, monosomy
What do aneuploidys result from
Meotic errors:
- usually in the mother during oegenesis
- can occur during spermatogenesis
What is the effect of maternal age on chance of autosomal trisomies.
Increases autosomal trisomes
What is Down’s syndrome caused by
An extra copy of chromosome 21= trisomy 21
What would 47,XX +21 denote
Person has 47 chromosomes Including XX (female) One extra ch. 21 = Down’s syndrome
How do chromosome errors occur in Meiosis
Abnormalities in how the chromosomes segregate from one another in meiotic divisions
What is non - disjunction (in mieotic errors)
Failure of chromosome or chromatid speration
What happens in meiosis error I in a non disjunction
Both of the chromosomes segregate into a single cell rather than one into each cell
- gives rise to two disomic gametes and two nullsomic gametes
What happens in in a mieosis II error
Chromatid non disjunction - the two sister chromatids from one of the cells doesn’t separate properly
- results in one disomic, one nullisomic, two normal gametes
Disomic and normal gamete can result in
Fetal trisomy (may be viable)
Monosomic (none) and normal can result in
Fetal monosomy (lethal)
Name three viable autosomal trisomies
Down’s syndrome = t21
Patau syndrome = t13
Edwards syndrome = t18
Symptoms of Down’s syndrome (trisomy 21)
Heart malformations Learning difficulties Gut atresia Early dementia Leukaemia 1/700
Symptoms of patau syndrome (trisomy 13)
Microcephaly Severe Holopresencecephaly = brain dev. Abnormalitiy Clefting Polydactyly Rare (1/5000) Unlikely long term survival
Symptoms of trisomy 18 = Edwards syndrome
Microcephaly Clenched hands Rocker bottom feet Cardiac anomalies 1 in 5000
Polydactyly is symptom of which trisomy
Patau syndrome (T13)
Rocker bottom feet and clenched hands are symptoms of whihc trisomy
Edwards syndrome = T18
If all anueploidies are possible, why are only 13, 18 and 21 viable and the rest lethal
The genes on these chromosomes (13, 18, 21) are less dosage intolerant
What happens in sex chromosome aneuploidy in regards to X inactivation
One X chromosome is inactivated cos of dosage compensation
What is the Karyotype for Turner Syndrome (sex ch. aneuploidy)
45, X (only one X chromosome)
Does Turner syndrome affect males and females
Females
Symptoms of Turner Syndrome
Short stature Infertility - primary ammenorrhea = absence of menstruation Foetal/ neonatal oedema Neck webbing Aortic coarctation 1/2500
Chromosomes in Klinfelter syndrome
47, XXY (males born with extra X chromosome)
Does klinfelter syndrome affect males or females
Males
Symptom of klinfleter syndrome
Male infertility
Polyploidy meaning
Whole extra haploid set of 23 chromosomes
Give two examples of when polyploidy is seen
Cancer cells
Abnormal conception in pregnancy
(Errors at fertilisation, extra chromosomes can be paternal or maternal)
What percentage of all pregnancies does polyploidy occur in
2%
What is digyny
When an unreduced maternal gamete (2n, sister chromatids haven’t separated properly) fertilises a reduced (normal, haploid) paternal gamete
= maternal extra chromosome
Symptoms of digyny
Growth retardati on in foetus and placenta and more
What is dispermy
Extra paternal chromosomes
2n from father but normal n from mother
Deletion meaning
Loss of chromosome segments
Duplicate meaning
Gaining extra chromosome material
Mosaicism meaning
Two or more cell populations with a different genotype exists in an organism
What is FISH and what is it sued for
Fluorescent in situ hybridisation
- can visualise and map the genetic material in cells, including specific genes or portions of genes
How does FISH work
- Prepare short sequences of single stranded DNA that match the portion of the gene you’re interested in/ looking for = probes.
- Label the probes each with a different colour of Florescent dye
- Since these probes are single stranded, they will bind to the persons complementary strand of DNA, wherever it resides on the individuals chromosomes.
- Therefore, the fluorescent tag provides a way for researchers to see its location.
What is G-banding used for
Technique used in cytogenetic to produce a visible karyotype by staining condensed chromosomes - useful for identifying genetic diseases through the photographic representation of the entire chromosome complement.
What is whole genome sequencing
Method for analysing entire genomes
Advantages of WGS
- provides high resilsltion, base by base view o the genome
- captures large n small variants that may be missed with targeted approaches
- identifies potential causative variants
- gives large volumes of data in short time
What kinds of things can WGS detect
Single nucleotide variants, insertions/ deletions, CNV, large structural variants
What is chromosomal microarray
Looks for CNVs:
Duplications and deletions
( eg, trisomy such as Down’s syndrome, monosomy)
How does microarray work
Probes and the patients DNA are hybridised
- probes bond to specific chromosome regions
- computer analysis is sued to compare n=genetic material with the reference sample - difference = variant
What is QF- PCR
Quantitative Fluorescent PCR is a molecular test for the identification of common aneuploidy syndromes: 13, 18, 21
How does QF- PCR work
Specific DNA markers (Short Tandem Repeats) are found across the chromosomes.
In this method, 3-5 STR markers across chromosomes 13, 21, 18 are amplified by PCR
The primers used for amplification are have different coloured fluorescent tags and the amplification products are different sizes.
The amount of fluorescence and size of DNA that’s been copied is measured and presented graphically.
Number of peaks/ height of each peak shows teh number of copies of alleles at that region of the chromosome in that DNA sample.
What test can be used to test for DiGeorge syndrome
FISH as it can detect micro deletion
(DiGeorge syndrome has 2- Mb deletion of chromosome 22q11.2
Does fish or g banding have higher resolution
Fish
What is a novel junction
Place where the extra genetic material meets the existing one in duplication of a gene
Which molecular test is important for during pregnancy
QF PCR
What is a pericentric inversion
If both breakpoints are on different arms
‘Around the centromere’
Inversion meaning
When DNA breaks away and attached in a different place in the same chromosome - no loss/ gain of genetic material
What is a paracentric inversion
Both breakpoints are on teh same arm
Doesn’t Invlove the centromere
What is haploinsufficneiny
How intolerant of a loss of copies that specific gene is =
Low scores = greater likelihood of pathogenicity
Why are cytogenetic analysis needed rather than DNA tests sometimes
For genome arrangements eg, translocations
Eg, WGS/ array CGH wouldn’t pick up on balanced reciprocal arrangements as no change in ‘amount’ of material
What is a balanced reciprocal rearrangement
Both chromosomes swap segments
No change in amount of DNA material
So this can only be picked up by detecting that abnormal junction DNA sequence
What is a reciprocal translocation
Breaks and exchanges - may show no abnormality
Abnormality risk = 5-10%
Reproductive risks
1/ 500 normal individuals
What is mietoic quadrivalent / pachytene cross
The way the the homologous segments match up/ pair at mieosis (the way they then segregate determines if its a balanced or not segregation)
Why is an alternate segregation of the pachytene cross balanced
Divides in ‘an opposite cross going away’ so there is an equal amount of each chromosome
Why is adjacent segregation unbalanced
Divides ‘up and down’ so the there is an unequal number of each chromosome on each divided side
What is a Robertsonain translocation
Chromosome attaches to teh other, whole arm fusion
Reproductive risk
1/1000 normal
Acrocentric (short arm loss)
What do the short arms of ch, 21 and 22 contains
No unique genes
RDNA nad satellite repeats
What is 47, XX, +21
Down’s syndrome
