Learning outcomes
Understand the approaches used to analyze chromosome abnormalities and the relative advantages and disadvantages of each approach
Karyotype
Arrest cells in metaphase, stain, and look at through a microscope.
Typically used when looking at whole chromosomes and haploid genomes.
Resolution of 108 through 109 base pairs
Fluorescence in situ hybridization (FISH)
Useful to see a submicroscopic region using a probe
Resolution of 104 to 105 bp
Microarray
Can represent an entire genome
Have to use both DNA from a patient and reference DNA, then hybridize. The resulting color indicates a gain or loss in a chromosome
You don’t get any information about the location or arrangement of the change.
High resolution
Whole genome analysis
Gives information about aneuploidy, duplications, deletions, single base pair changes, translocations, and inversions.
Not useful if you’re looking for a mutation in one gene because it’s hard to interpret.
Highest resolution
Be able to describe conditions that motivate screening for chromosome abnormalities
Family history
Fertility problems
Stillbirth or neonatal death
Early growth/development problems
Cancer
Pregnancy
Understand the clinical implications of aneuploidy and be able to explain how defects in meiosis lead to errors in chromosome number
Trisomy or monosomy
Usually causes spontaneous abortion
Developmental abnormalities due to altered gene dosage
Usually due to meiotic nondisjunction
Understand the difference between balanced and unbalanced chromosome rearrangements and their clinical implications
Balanced rearrangements: do not change relative gene dosage
includes many inversions and translocations
Unbalanced rearrangements: Too many or too few copies of some genes
Most deleterious
Be able to describe common chromosome abnormalities
Robertsonian translocations
Most common structural chromosome abnormality in humans
1/1000 live births
Involves 2 acrocentric chromosomes
Carriers have a normal phenotype but may have a high rate of miscarriages, difficulty conceiving, or stillbirths.
Understand how balanced chromosome rearrangements can lead to the production of aneuploid gametes
Balanced chromosomes can’t line up normally during meiosis because they aren’t real homologues.
The chromosomes form a quadrivalent
Has the chance of creating normal/balanced offspring, but higher chance of unbalanced, leading to abortion.
Should have a general understanding of the frequencies of chromosome abnormalities and their consequences
Key terms
Aneuploidy
Extra or missing chromosomes
Structural abnormalities
Includes deficiencies, duplications, translocations, inversions, and other complex rearrangements
Chromosome abnormalities
Often alter relative gene dosage
Occur in 1% of live births
2% of all pregnancies in women over 35
Cause 50% of spontaneous abortions in women
Trisomy
Monosomy
Fluorescence in situ hybridization
Chromosomal microarray
Whole genome sequencing
Meiotic nondisjunction
Balanced rearrangement
Unbalanced rearrangement
Interstitial deletion
A deletion in the middle of a chromosome
Terminal deletion
A deletion of the end of a chromosome
Isochromosome
When the arms of the chromosome are mirror images of each other
Ring chromosome
Robertsonian translocation
Reciprocal translocation
Paracentric inversion
Centromere does not lie in inversion
Pericentric inversion
Centromere does lie in inversion