Day 4, Lecture 2: Genetics V: Human Chromosome Abnormalities Flashcards
Clinical Cytogenetics
- Study of the relationship of chromosomal alterations and genetic diseases in human beings
Chromosomal abnormalities cause
- Pregnancy loss
- Congenital malformations
- Intellectual disabilities (Mental Retardation)
- Play a role in the pathogenesis of malignancy
How common are chromosome abnormalities
- about 1% of live births
- about 50% of first trimester miscarriages
Classification of cytogenetic mutations
Numerical Chromosome Abnormalities
What is the most common chromosome abnormality seen in live births?
- Trisomy 21
- Incidence 1 out of every 691 live births
- Can happen to women of all ages, races and economic levels
Causes of Trisomy 21
- Caused by having 3 compies of chromsome 21
- 95% is nonfamilial Trisomy 21
- 3-4% is unbalanced translation
- only 1% are familial unbalanced translocation
- 1-2% is mosaicism with two cell lines- normal and trisomy 21
Common Aneuploidy Conditions
- Autosomes
- Trisomy 21
- Trisomy 18
- Trisomy 13
- Sex Chromosomes
- Monosomy X
- Klinefelter Syndrome
Clinical Features of Trisomy 21
What is Mosaicism?
- The situation in which not all cells in an organism possess the same genotype. Mosaicism usually occurs as the result of postconceptional (acquired) changes.
Trisomy 18 (Edwards Syndrome)
Trisomy 13 (Patau Syndrome)
Monosmy X (Turner Syndrome)
Klinefelter Syndrome (47, XXY)
Do Chromosome aneuploidy conditions usually run in families?
- No, it is a sporadic event
Structural Abnormailities
What is an Isochromosome?
One arm is duplicated forming two arms with a shared centromere
Chromosomal Translocations
Microdeletion Syndromes bridge the gap between
- Single gene and chromosomal syndromes
- The deletion of a megabase or so is too small to be seen under the microscope, however, it may involve a dozen or more genes
- FISH analysis and chromosome microarray are revealing increasing numbers of such submicroscopic chromosomal abnormalities
Molecular pathology puts deletions/duplications into what three categories
microdeletion syndromes, contiguous gene syndromes, and segmental aneuploidy are now generally referred to as
- Genome disorders
- (note: Genome disorders have a complex phenotype (frequently includes mental retardation, developmental delay, and behavioral problems) due to alteration of gene dosage)
- Haploinsufficiency
- Deletion (majority of genome disorders)
- Terminal deletion (telomeric)
- Imprinting or UPD
- Overexpression
- Duplication (minority of genome disorders)
- Haploinsufficiency
- (note: Genome disorders have a complex phenotype (frequently includes mental retardation, developmental delay, and behavioral problems) due to alteration of gene dosage)
Mechanism of genome disorders
- Usually less than 5Mb is involved in the deletion or duplication that leads to a genome disorder
- Areas of high recombination are often flanked by unique low copy repeats
- Due to the low copy repeats, the chromatids misalign during recombination in meiosis
- This misalignment leads to non-homologous recombination and unequal crossing-over
Can a child inherit a microdeletion syndrome from a parent?
Yes
Williams Syndrome
Langer-Giedon Syndrome
DiGeorge Syndrome
Duplication 22q syndrome
Prader-Willi Syndrome
Angelman Syndrome
Genetics of Prader-Willi/Angelman Sydrome
1p36 Deletion Syndrome
Cri-du-Chat Syndrome
Wolf-Hirschorn Syndrome
Smith-Magenis Syndrome
Chromosome Analysis
Karyotype
Metacentric
- Centromere is central with arms being almost equal length
Submetacentric
Off-centered centromere with arms being different lengths
Acrocentric
Centromere is near one end
Fluorescence in situ hybridization (FISH)
- Uses fluorescent probes that bind to only those parts of the chromosome indicated for study
- Used to detect microdeletion syndrome, aneuploidy, unknown chromosome material seen on karyotype
explain how FISH is able to show a deletion syndrome
- A chromosome reporter probe is able to show which chromosome you are looking for a deletion at
- A critical region probe will attach if the genes are there and will not attach if they have been deleted (example in the picture)
Chromosome Microarray analysis (aka Comparative genome hybridization (CGH))
- Genome-wide screening
- used to measure the differences between two different DNA samples (control and test) in copy number, or dosage, of a particular DNA segment
- Limitations:
- Cannot detect balanced rearrangments
- Cannot provide the physical location of copy-number variants of unkown clinical significance
- Cannot detect low levels of mosaicism
Specimen Types for Chromosome Analysis
- White blood cells in peripheral blood
- preferred specimen type
- Fibroblasts from skin biopsy
- Solid tumor biopsy
- Bone marrow
- Fetal cell derived by
- amniocytes from amniotic fluid
- Collected via a procedure called amniocentesis
- Chorionic villus cells
- Collected via a procedure called chorionic villus sampling
- Fetal blood
- Collected via a procedure periumbilical blood sampling
- Products of Conception
- amniocytes from amniotic fluid
Abbreviations used to describe chromosome and their abnormalities
