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What is clinical cytogenetics?

The study of abnormalities of chromosome number and structure in relation to human disease


True or false - cytogenetic abnormalities are collectively more common than all Mendelian single gene disorders.



Cytogenetic abnormalities account for ___ live births.



The incidence of cytogenetic abnormalities in children of mothers >35 years old is ___.



What are the 6 major indications for cytogenetic analysis?

1. Problems with early childhood growth and development (failure to thrive, abnormal physical appearance and/or internal structural abnormalities, mental retardation, ambiguous genitalia)
2. Stillbirths and neonatal deaths that have the appearance of a cytogenetic abnormality
3. History of infertility or recurrent miscarriage
4. Known or suspected chromosome abnormality in a first degree relative
5. Maternal age >35
6. Cancer


What are the common types of dividing nucleated cells or tissues used for cytogenetic analysis?

1. White blood cells (T lymphocytes) from peripheral blood
2. Amniotic cells
3. Cell of the chorionic villi (extra-embryonic fetal tissue that form the surface of the chorionic sac)
4. Fibroblasts
5. Cancer cells
6. Bone marrow


How are chromosomes classified?

By position of centromere


What are the 3 classifications of chromosomes?

1. Metacentric: centromere found midway
2. Submetacentric: centromere off-center, arms of equal length
3. Acrocentric: centromere very near on end, produces p arm known as a satellite


What are the 5 acrocentric chromosomes in humans?

13, 14, 15, 21, 22


Acrocentric satellite arms contain many copies of genes coding for ___.



___ created by various staining procedures are unique to each chromosome.

Banding patterns


Which chromosome arm is longer? Which is shorter?

q; p


How are chromosomes numbered?

Example: 1p12 = chromosome 1, p arm, region 1, band 2 - note that regions are numbered from the centromere to the telomere


Normally, staining occurs during ___. However, higher resolutions are obtained when chromosomes are less condensed and are in ___.

Metaphase; prophase or prometaphase


What are the properties of dark bands stained with Giemsa?

1. Stains strongly with quinicrine
2. Maybe AT-rich
3. Early condensation, late replication
4. Gene poor
5. Alu poor, LINE rich


What are the properties of pale bands stained with Giemsa?

1. Stains weakly with quinicrine
2. Maybe CG-rich
3. Late condensation, early replication
4. Gene rich
5. LINE poor, Alu rich


What are several alternative chromosome staining methods?

1. Q-banding (uses quinicrine, correlates to G-bands)
2. R-banding (reverse Giemsa pattern)
3. Fluorescence R-banding (fluorescent bands correlate to light bands in Giemsa)
4. Prometaphase banding (higher resolution, G or R-banding)


What do the following abbreviations stand for regarding the description of chromosomal abnormalities?
1. ,
2. -
3. ( )
4. +
5. ;
6. del
7. der
8. dic
9. dup
10. fra
11. i
12. ins
13. inv
14. .ish
15. mar
16. mat
17. p
18. pat
19. q
20. r
21. rob
22. t
23. ter

1. separates chromosome number, sex chromosome, chromosomal abnormalities
2. loss of chromosome
3. surround structurally altered chromosomes/break points
4. gain of chromosome
5. separates rearranged chromosomes and breakpoints involve more than one chromosome
6. deletion
7. derivative chromosome (translation chromosome derived from 1 chromosome and containing its centromere)
8. dicentric chromsome
9. duplication of a portion
10. fragile site
11. isochromosome (arms are the same)
12. insertion
13. inversion
14. precedes karyotype results from FISH
15. marker chromosome (unidentifiable piece)
16. maternally derived chromosome rearrangement
17. short arm
18. paternally derived chromosome rearrangement
19. long arm
20. ring chromosome
21. Robertsonian translocation
22. translocation
23. terminal end of arm


What are aneuploidies?

Abnormalities of chromosome number; most common type of human chromosome disorder


What is the frequency of aneuploidies in all pregnancies?



___ are incompatible with live births.

Autosomal monosomies


Only 3 autosomal trisomies are capable of producing a live birth. What are they, what syndrome do they produce, and what is the frequency?

1. Trisomy 13 (Patau syndrome) - 1/22,700 live births
2. Trisomy 18 (Edward syndrome) - 1/7,500 live births
3. Trisomy 21 (Down syndrome) - 1/580 live births


Why can trisomies 13, 18, and 21 still result in a live birth?

These three chromosomes contain the smallest number of genes.


True or false - most common sex chromosomal aneuploidies are incompatible with life.

False - most are compatible with life


What are two female aneuploidies?

1. Turner Syndrome, monosomy X (45, X), 1/4000 female births
2. Trisomy X (47, XXX), 1/900 female births


What is the frequency of all X chromosome aneuploidies?

1/580 female births


What are two male aneuploidies?

1. Klinefelter syndrome (47, XXY, 48 XXXY), 1/1000 male births
2. 47, XXY syndrome - 1/1,000 male births


What is the frequency of all X or Y aneuploidies?

1/360 male births


Aneuploidy is commonly caused by meiotic nondisjunction. What is this?

The failure of chromosomes to detach from each other during one of the two meiotic divisions.


What is the result of meiotic nondisjunction in meiosis I? In meiosis II?

I: produces gametes with 1 maternal copy and 1 paternal copy of the extra chromosome.
II: produces a gamete with either 2 maternal or 2 paternal copies of the extra chromosome.


What are the two types of unbalanced rearrangements?

1. Partial trisomy - presence of an extra copy of a portion of one chromosome, caused by duplication or insertion
2. Partial monosomy - presence of a missing portion of one chromosome, caused by a deletion


Duplications and deletions can result from...

...unequal crossover between misaligned sister chromatids or homologous chromosomes that contain long repeated stretches of highly similar DNA sequences.


Unbalanced rearrangements can result from generation of an ___, which contains 2 of the same arm.



What is the most common isochrome?

X chromosome with 2 q arms; 15% of women with Turner syndrome have this genotype


Unbalanced rearrangements can also result from formation of ___ chromosomes. How does this occur?

Ring; results from a double strand break in each arm and attempted repair


Chromosomes lacking a centromere are ___; chromosomes containing 2 centromeres are ___. These are unstable - why?

Acentric; dicentric; unable to form kinetochore/attach to mitotic spindle (acentric) or subject to destruction as 2 centromeres will be pulled to opposite poles of dividing cell (dicentric)


Those with balanced rearrangements are unlikely to have an abnormal phenotype. Why? What is the exception to this?

All chromosomal material is present; when an essential gene is disrupted.


What is an inversion and what are the two types?

Occur when a single chromosome undergoes 2 breaks and the segment between the breaks inverts; paracentric (break occurs in the same arm, leads to normal or balanced chromosomes) and pericentric (breaks occur in opposite arms, leads to normal, balanced, or unbalanced chromosomes)


What are reciprocal translocations?

Carriers are balanced and usually unaffected unless break points disrupt an essential gene. However, balanced translocations are associated with a high risk for unbalanced gametes and abnormal progeny.


In reciprocal translocations, 2:2 segregation leads to ___. 3:1 segregation leads to ___.

1 normal, 1 balanced, 4 unbalanced; all (8) unbalanced


What is a Robertsonian translocation?

Results from crossover of long stretches of repeated DNA in the short arms of acrocentric chromosomes that encode rRNA; both centromeres are present, but function as 1; small fragment is lost. The carrier is asymptomatic but can produce unbalanced gametes.


What are the products of a Robertsonian translocation?

1 normal, 1 balanced, 2 trisomy, 2 monosomy


Microdeletions and duplications result from...

...unequal crossing over between misaligned sister chromatids or homologous chromosomes containing highly similar DNA sequence repeats.


What are the different chromosomal/gene techniques and their resolution levels?

1. Standard karyotyping - haploid genome/whole chromosome
2. Routine banding - 440-450 chromosome band
3. High-resolution banding - 850 chromosome band
4. Comparative genome hybridization, FISH, chromosomal microarrays - submicroscopic region
5. Whole genome sequencing - nucleotides


___ can be used to detect gross chromosomal abnormalities and small deletions/duplications.



___ can be used to detect chromosome and genomic dosage based on ___.

Chromosomal microarrays; comparative genome hybridization


Why is genomic imprinting utilized?

Some gene products are harmful at a high dose, so 1 of the 2 alleles must be turned off during devlopment.


In imprinting, one parent passes on an ___ version and the other parent passes on an ___ version.

Active; inactive


The imprinted state persists in most tissues until after ___ and during ___.

Fertilization; postnatal development


What inactivates genes in imprinting?

CpG methylation in the promoter region of the gene


When a female child inherits a paternally imprinted allele, she must reverse the imprint in germ cells to pass on the ___ imprint.



True or false - Prader-Willi syndrome and Angelman syndrome are sex-specific.

False; they can occur in either sex.


For 30% of PW patients and 5% of AS patients, the cause is not deletion or mutation, but ___.

Uniparental disomy (2 copies from 1 parent)