Lecture 26 Flashcards
What are the three most common chromosomal trisomies?
1) Down’s syndrome (trisomy 21)
2) Edward’s syndrome (trisomy 18)
3) Patao syndrome (trisomy 13)
What percentage of chromosomal abnormalities are present in miscarriages (SABs - Spontaneous Abortion), conceptuses (the embryo in the uterus, especially during the early stages of pregnancy) and liveborns respectively?
50%, 5% & 1%
Which is more harmful in general: A sex chromosome abnormality or an autosomal chromosome abnormality?
An autosomal chromosome abnormality
What is a requirement for a chromosome test to be done on a cell?
It must be nucleated (RBCs have no nucleus)
What are the most common cell types that undergo chromosomal testing?
Blood lymphocytes, amniocytes, fibroblasts and bone marrow cells
What is the most frequently used stain for chromosomal testing?
Giemsa stain
How are lymphocytes chromosomally tested?
1) A blood sample is added to culture media
2) Red blood cells are removed
3) T-cell division is stimulated
4) The cells are “frozen” in metaphase
5) The cells are lysed and dropped onto slides for analysis
What is Fluorescence in situ hybridization (FISH) used for?
To identify trisomies (extra chromosomes) or microscopic deletions in interphase or metaphase cells
What can be used to uncover complex chromosomal rearrangements?
Chromosomal paint - refers to the hybridization of fluorescently labeled, chromosome-specific, composite probe pools to cytological preparations; Usually used for cancer cells
What is Comparative genomic hybridization (CGH) used for?
To identify subtle chromosomal deletions and duplications
What is Comparative genomic hybridization (CGH)?
Comparative genomic hybridization is a molecular cytogenetic method for analyzing copy number variations relative to ploidy level in the DNA of a test sample compared to a reference sample, without the need for culturing cells (ratio between actual DNA and test DNA should always be 1:1 if they are normal)
What is the proper way to assign Cytogenetic nomenclature?
1) # of chromosomes or chromosomal units
2) Sex chromosome complement
3) Any structural or numeric variation not otherwise specified
What is SAB?
Spontaneous abortion or miscarriage
What is IUGR?
Intrauterine growth retardation (restriction)
What is MCA?
Multiple congenital anomalies
What is SS?
Short stature
What is ID?
Intellectual disabilities
What is LD?
Learning disabilities
What is ADHD/ADD?
Attention deficit hyperactivity disorder/Attention deficit disorder
What are signs of a prenatal chromosomal abnormality?
1) IUGR
2) MCA
3) hydrops/edema
What are signs of an infantile/childhood chromosomal abnormality?
1) MCA
2) unusual facial features
3) SS
4) ID
5) LD
6) ADHD
What are signs of an adulthood chromosomal abnormality?
1) LD
2) infertility
3) SABs
4) stillbirths
What is the anatomy or phenotype of a cytogenetic variation?
Fools Believe Genes are Disposable
F - Facial Features (dysmorphic)
B - Birth defects and physical variations
G - Growth retardation including head growth
D - Developmental problems
When does Trisomy 21 (Down’s Syndrome) become more common?
Non-disjunction that results in Down’s syndrome is associated with increasing maternal age.
Although most trisomy 21 cases are caused by non-disjunction, when is a robertsonian translocation most often seen?
In younger mothers with trisomic offspring; chromosome 21 is an acrocentric chromosome
What are features of trisomy 21?
F - epicanthal folds, upslanting palpebrae
B - septal heart defects
What percentage of trisomy 18 individuals are born?
5%
Of all liveborns with trisomy 18, __% die in the first weeks of life, __% by two months and __% by one year of age
50%, 60%, & 95%
What are key features of trisomy 18?
F - bird-like facies
B - rocker bottom feet
G - IUGR
Severe intellectual disabilities in survivors as well
About ___% of Trisomy 13 individuals are due to a Robertsonian translocation
20%; chromosome 13 is an acrocentric chromosome
About __% of trisomy 13 individuals die in the first month of life
50%
What are key features of trisomy 13?
B - holoprosencephaly, oro-facial clefts, & extra finger/toes (polydactyly)
G - IUGR
What is chromosomal mosaicism?
1) Mosaicism = more than one chromosomally distinct cell line in the same individual
2) Most often arise during early embryonic life with loss of a chromosome or unequal chromosomal segregation
What is one of the most common cytogenetic deletions?
4p- (Wolf-Hirschhorn)
What are key features of Wolf-Hirschhorn (4p-)?
F - helmet nose, arched eyebrows
B - oro-facial clefts
G - microcephaly (small head)
What is a microdeletion or “contiguous gene” syndrome?
Results from small, sometimes submicroscopic deletions of genetic material
What is a very common microdeletion?
22q11.2 deletion (DiGeorge syndrome, velocardiofacial syndrome)
Why do individuals with microdeletions have similar physical features?
Loss of adjacent genes within the deletion region
What are key features of 22q11.2 deletion (DiGeorge syndrome, velocardiofacial syndrome)?
F - long narrow face
B - conotruncal heart defects (major vessels), parathyroid gland function (hypocalcemia), T-cell defects (immunodeficiency), long tapered fingers
D - mild ID or LD
When must a cytogenetic duplication always occur?
For every microdeletion there should be an equal and opposite microduplication
What can be used to test for cytogenetic duplications?
Comparative genomic hybridization (CGH) to identify subtle chromosomal abnormalities
What does an unbalanced translocation usually result in?
An unbalanced translocation usually results in a duplication (partial trisomy) and deletion (partial monosomy) of genetic material
What does hemizygous mean?
Males only have a single X chromosome, so they are termed hemizygous
Do females on average produce any more or less protein products for most genes because they have two X chromosomes?
No; One X chromosome is inactivated. However about 10 to 15% of genes on the X chromosome escape inactivation, especially on Xp
Does the Y chromosome have any satellites?
No
The Y chromosome replicates ____ than other acrocentric chromosomes
later
What is a distinctive gene on the Y chromosome?
1) Testis determining factor that is responsible for male sexual differentiation
2) Also has genes for height, tooth size and hair growth in external ear
Why are sex chromosome problems more common than autosomal chromosome problems?
Not as fatal
If a mother does not have prenatal testing, will a sex chromosome aneuploidy for her baby be identified at birth?
Mostly no
Are sex chromosome variations usually associated with intellectual disability?
No, but affected individuals can have mild developmental problems
What is Turner syndrome?
Turner syndrome is a genetic condition in which a female does not have the usual pair of two X chromosomes
What causes Turner syndrome?
Most often results when a normal egg is fertilized by a sperm without a sex chromosome
What can Turner Syndrome lead to?
Ovarian failure and short stature
What are key features of Turner Syndrome?
F - webbed neck
B - coarctation of the aorta
G - SS in childhood
D - LD and/or visual-spatial perceptual problems, infertility due to ovarian failure
What does Triple X syndrome result in?
1) No physical feature at birth (no recognized phenotype)
2) Mild LD and increased risk for psychiatric disorders
3) Usually normal fertility but increased risk for premature ovarian failure
What does Klinefelter syndrome (47 XXY) result in?
1) Increased risk for mild LD
2) Behavioral and socialization difficulties
3) Breast enlargement (gynecomastia), small testes and infertility
What does (47 XYY) result in?
1) Mild LD, ADHD & behavioral problems
2) Tall stature may be seen
3) Normal fertility
What can happen during an X chromosome translocation with an autosome?
The normal X chromosome may appear to be preferentially inactivated. This most likely results from “selection” or non-viability of cells with the translocated or derivative X inactivated. It can result in expression of an X-linked recessive condition in a female
How can a female express an X-linked recessive disorder?
1) By inheriting two copies of the recessive gene - one from each parent (a double dose)
2) X autosome translocations with cellular “selection” or non-viability
3) Turner syndrome
4) Manifesting heterozygotes may also result from unfavorable or skewed X-inactivation for single gene disorders such as Duchenne muscular dystrophy or hemophilia
If a child has multiple congenital anomalies, poor growth, and ID, what chromosomes are you concerned about?
Autosomal chromsomes
If an individual has mild learning problems, social difficulties and/or fertility problems, what chromosomes are you concerned about?
Sex chromsomes
