Wk6 Chromosome Abnormalities Flashcards
What is a chromosome?
A chromosome is made of a single molecule of DNA
Each chromosome has hundreds of genes along its length
What is a gene?
- A specific stretch of DNA where the sequence contains genetic instructions is a gene
- Genes are arranged one after the other along the DNA of a chromosome, with stretches of non- coding DNA between them
Structure - telomere
DNA and protein cap
Ensures replication to tip
Tether to nuclear membrane
Structure - light bands
Replicate early in S phase
Less condensed chromatin
Transcriptionally active
Gene and GC rich
Structure - centromere
Joins sister chromatids
Essential for chromosome segregation at cell division
100s kilobases of repetitive DNA: some non-specific, some chromosome specific
Structure - dark G bands
Replicate late
Contain condensed chromatin
AT rich
How do we examine chromosomes?
- Karyotype from peripheral lymphocytes
- Fluorescent in situ Hybridisation (FISH)
- Array CGH - comparative genomic hybridisation -
What type of chromosome abnormalities are there?
- abnormalities of chromosome number
- abnormalities of chromosome structure
- chromosome abnormalities are also classified according to which cells of the body they are distributed in
Constitutional = all cells of the body
Somatic = only in certain cells/tissues of the body
How do abnormalities of chromosome number occur?
Aneuploidy
- trisomy
- monosomy
Polyploidy
- triploidy
- tetraploidy
Why is there an increased risk of meiotic error leading to trisomies in geriatric pregnancies?
- the stock of oocytes is ready by 5 months gestation. Each remains in maturation arrest at the crossing-over stage until ovulation
- there may be a lengthy interval between onset and completion of meiosis (up to 50 years later)
- accumulating effects on the primary oocyte during this phase may damage the cell’s spindle formation and repair mechanisms predisposing to non-disjunction
Clinical consequences of chromosomal abnormalities
- abnormalities of chromosome number have significant often lethal consequences
- significant development abnormalities occur due to the imbalance of gene products
- the effect of reducing the gene copy usually has more severe consequences than increasing the gene copy
What are the most frequent numerical anomalies?
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
What is the genetic basis of Down syndrome?
- 95% people have 3 separate copies of chromosome 21: trisomy 21
- 4% have the extra copy of C21 because of a robertsonian translocation
- 1% have mosaicism with normal and trisomy 21 cell lines (and usually have much milder features because of the presence of the normal cells)
How does having 3 copies of gene cause DS?
- “ gene dosage effect” - features of syndrome caused by 1.5x amount of specific gene products from chromosome 21
- “amplified developmental instability” - features of syndrome caused by overall effect of imbalance on development
What are the implications for genetic counselling?
- aneuploidy is usually the results of meiotic non disjunction related to maternal age
- the risk of recurrence is therefore low and will be related to age of the mother
What is a robertsonian mutation?
Breakage of 2 acrocentric chromosomes (13, 14, 15, 21, 22) at or close to their centromeres with subsequence fusion of their long arms - short arms are lost
Balanced = no effect on phenotype as no gene imbalance Unbalanced = e.g. Down syndrome
What is the probability of recurrence for robertsonian translocations?
- carrier for 14:21 has a high theoretical probability of having a child affected with DS
- but the observed figure is less than predicted
- also compared with low recurrence in regular trisomy DS due to error in cell division
- this is why it is importance to karyotype a person with DS - to determine chromosomal cause
What is a reciprocal translocation?
Breakage of 2 non-homologous chromosomes with exchange of the fragments
Any chromosomes can be involved
Outcome of normal zygote
Normal
Outcome - normal but unbalanced translocation but balanced carrier
Risk to children
Outcome of partial trisomy + partial monosomy
Miscarriage, congenital malformation, developmental delay, mental abnormality
Outcome of Partial monosomy + partial trisomy
Miscarriage, congenital malformation, developmental delay, mental abnormality
What are the probabilités of recurrence for reciprocal translocations?
The size and position of the chromosome segments involved in the translocation may have an effect on:
- the pairing of the chromosomes at meiosis
- Frequency of different forms of translocation in the gametes
- the likelihood of the concept us with that abnormality developing to thermal
What are large chromosome délitions/duplications?
Can occur because of unequal crossing-over in meiosis following mis pairing (often at the sites of repeated sequences)
What is mosaicism?
Two populations of cells with different genetic constitutions usually as a result of an error in mitosis
What is somatic mosaicism?
Two populations of cells in body
What is somatic mosaicism?
Two populations of cells only in the gonads
