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categories of chromosome abnormalities
numerical & structural
most common category of genetic disease
chromosome abnormalities: specific chromosome abnormalities are responsible for 100\'s of identifiable syndromes that are collectively more common than all the single mendelian single-gene disorders together
2 major categories of genetic disease
chromosome abnormalities & single gene disorders
percentage of live births with cytogenetic disorders
1 percent of live births
percentage of pregnancies in advanced age with cytogenetic disorders
2 percent
percentage of spontaneous first trimester abortions with cytogenetic disorders
approximately 50 percent
best specimen for routine chromosome analysis
peripheral blood (white blood cells), specifically T-lymphocytes
steps of routine karyotyping
Collect peripheral blood in heparin culture metaphase arrest (colchicine) hypotonic solution (spread chromosomes and lyse red blood cells) fix cells spread on slide stain
six clinical indications for chromosome analysis
problems of early growth and development stillbirth & neonatal death fertility problems family history neoplasia pregnancy in a woman of advanced age
advanced maternal age
greater than 35
best specimen for long term culture
fibroblasts (skin biopsy)
example of immortal cell-line from peripheral blood
lymphoblastoid cell line
disadvantage of bone marrow 4 chromosome analysis
poor resolution & difficult analysis
advantage of bone marrow specimen 4 chromosome analysis
high proportion of dividing cells so little if any culture required
Cells that require little if any culture
CVS Bone marrow
number of types of chromosomes in human genome
24
3 main types of chromosomes banding
G-banding Q-banding R-banding
G-banding
(giemsa banding) the most common method used in clinical laboratory
Q-banding
(quinicrine mustard banding) like G-banding except examined by fluorescence microscopy
R-banding
(reverse banding) requires special treatment such as heating before staining, resulting in dark and light bands that are reversed of those produced by g or q banding
advantage of R-banding
pattern that is easier to analyze then that given by g or q banding (europe)
Heteromorphisms
a normal morphological or staining variant of a chromosome
advantage of q & c-banding
useful for detecting heteromorphisms
Ways in which chromosomes are identified
size placement of centromere banding pattern
categories of centromere placement
metacentric, submetacentric,and acrocentric
acrocentric chromosomes (5)
13, 14, 15, 21, 22
secondary constrictions in acrocentric chromosomes
narrow stalks to which satellite are attached to short arms which contain hundreds of copies of genes encoding ribosomal RNA & other repetitive sequences
C-banding
staining of centromeric region of each chromosome and others regions containing constitutive heterochromatin
Constitutive heterochromatin
1q, 9q, and 16q adjacent to centromere and distal part of Yq
heterochromatin
chromatin defined by its property of remaining in the condensed state and staining darkly in non dividing (interphase) cells
high-resolution banding AKA? and definition?
"prometaphase banding" achieved through G or R banding at earlier stage of mitosis to get increased resolution (550-850) bands vs 450 (standard metaphase)
fragile site
non-staining gap in DNA at characteristic sites on several chromosomes, which break when exposed to growth conditions or chemicals that alter or inhibit DNA synthesis.
most famous heritable "fragile site"
End of Xq in males with Fragile X Syndrome.
First "molecular cytogenetic" technology
FISH
CGH (comparative genome hybridization)
array-based CGH method that allows for measurement of relative copy number of DNA sequences as compared to control samples.
Common genomic location for copy number polymorphisms or variants
subtelomeric and centromeric regions of chromosomes
Most common type of clinically significant chromosome abnormality
Aneuploidy
reciprocal translocation
Relatively common abnormality in which there is exchange of segments between non-homologous chromosomes, usually with no phenotypic effect but increased risk of abnormal offspring
Appropriate response to abnormal CGH
Confirm abnormality with FISH or karyotype
Types of inversions?  which is worse
Pericentric (worse, risk of birth defect in offspring increases with size of inversion) & peracentric (very low risk of abnormal phenotype)
Which is worse?  Monosomies or trisomies
Monosomies (not viable except for Turner S.)
Complete trisomies, which are viable
13, 18, 21, X, and Y
Predictability of mosaic?
"All bets off"
Ring chromosome
Rare abnormality, often mosaic, in which tips break off and ends unite
heteroploid
any chromosome number other than 46
euploid
exact multiple of the haploid chromosome number (n) (ie. 3n, 4n)
aneuploid
any "non-euploid" chromosome number
Cause of majority of triploidy (3n)
Dispermy (most) or failure of one of meiotic divisionst --> diploid egg or sperm
Triploid with extra set of paternal chromosomes
partial hydatiform mole
Triploid with additional set of maternal chromosomes
Early spontaneous abortion
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