Bioc L06 and L07 Cytogenetics

Question 1

What is cytogenetics?

Answer 1

The study of chromosomes and chromosomal
abnormalities

Question 2

How common are chromosomal abnormalities and what are some effects?

Answer 2

1/150 live births

leading cause of mental retardation

1st trimester: 50% of fetal losses

2nd trimester: 20% of fetuses lost

Leading known cause of pregnancy loss

Question 3

What is a karyotype?

How many chromosomes are in a normal somatic cell?

Answer 3

A microscopic photograph of chromosomes that have been histochemically arrested in metaphase. Used to visualize chromosome size and #

There are 46 chromosomes (23 pairs) in somatic cells and 23 single chromosomes in germ cells

Question 4

How are chromosomes classified after size?

Answer 4

By the position of the centromer, 3 types:

1. Metacentric
2. Submetacentric (short p-arms)
3. Acrocentric (stalk and satellite for p-arms)

Convention that the p-arm (shorter) will be on top in a karytope.

Question 5

What are acrosomes how many are there?

Answer 5

Acrosome are chromosomes with very short p-arms that connect to stalks and satellites. stalks encode ribosomal RNA

There are 5 acrocentric autosomes: 13, 14,15, 21 and 22

The q arm has repeat sequence and encodes ribosomal RNA, it can be damaged without much issue (ex: robertsonian translocation)

Question 6

What is a submetric chromosome?

Answer 6

A chromosome where the p and q-arms have unequal length.

Question 7

What is Fluorescent in situ hybridization (FISH)?

Answer 7

A way to view chromosomes.

A fluorescently labeled single‐stranded DNA segment
(probe) is exposed to denatured chromosome (either in
metaphase, prophase or interphase)

The probe undergoes complementary base pairing
(hybridization) only with the complementary DNA sequence and can be seen under a microscope.

Question 8

What is spectral karyotyping?

Answer 8

FISH with multiple colored probes for multiple chromosomes.

Question 9

What are 4 things FISH is used for?

Answer 9

1. microdeletions: see if DNA is missing
2. gene amplification: A flouescent band on one chromosome would be bigger than the flourescent band on the homologous chromosome
3. abnormal karyotype: e.g. finding and extra X chromosome
4. chromosome rearrangements: usually cancer cytogenetics, affected chromosomes would have 2 colors from reaaranging with another chromosome

Question 10

What is tetraploidy?

Answer 10

Cells that contain four copies (4N) of
 each chromosome (92 total)

Tetraploidy can be caused by a mitotic failure in the early embryo. All of the duplicated chromosomes migrate to one of the two daughter cells. It can also result from the fusion of two diploid zygotes.

Question 11

What is monoploidy?

Answer 11

The loss of a chromosome set, which is
not seen in humans.

Question 12

What is aneuploidy?

How is it caused?

Answer 12

The gain or loss of a specific chromosome (trisomy or monosomy)

Usually meiotic nondisjunction (two chromosome homologs migrate to same daughter cell)

All autosomal monosomies are lethal

Question 13

What autosomal trisomy of 3 diferent chromosomes it compatible with life?

Answer 13

Trisomy 13, 18 and 21 probably because those chromosome have the fewest genes.

Question 14

What trisomy (of one chromosome) is most compatible with life?

What are the symptoms?

How does it happen?

When is it more common?

Answer 14

Trisomy 21 because chromosome 21 contains the fewest genes.

Down syndrome

non-disjunction w/ extra chromosome contributed from the mother

It is more common with mothers giving birth after age 35, but, there are more down syndrom births from younger women because fewer older women have kids

Question 15

What is Edward Syndrome?

Answer 15

Trisomy 18, most lethal trisomy, only 10% alive after 1 year

Question 16

What is Platau Syndrome?

Answer 16

Trisomy 13, similar survival as Edwards

Characteristics include cleft lip, deafness, small head, developmental retardation

Question 17

Why are sex chromosome abnormalities more tolerated?

Answer 17

X-inactivation, if some phenotype is seen it’s due to incomplete x-inactivation.

since pseudoautosomal regions are not inactivated,
duplication or loss of these regions will result in increased or decreased gene dosage of these genes located in PARs.

Question 18

What is an example of an X monosomy?

Answer 18

Turner Syndrome 45,X

WIth only one X chromosome, there will only be one copy of the psudoautosomal genes resulting in half the psudoautosomal gene products

Symptoms include lack of sexual development, short stature, webbed neck, bent forearms

Question 19

What is Klinefelter syndrome?

Answer 19

Trisomy 47, XXY

Results in double psudoautosomal gene product.

Most common symptom is infertility in men.

Question 20

What pairs between X and Y chromosomes during recombination?

Answer 20

The pseudoautosomal regions: (PAR1 and PAR2)

The SRY (sex‐determining region on the Y) is proximal to PAR1

Question 21

How can there be XX males?

Answer 21

From aberrant recombination in the father between the X and Y chromosomes transferring the SRY gene to the X chromosome. Offspring with XX that would normally be female are male.

Question 22

How can there be XY females?

Answer 22

Same reasons as XX males but offspring inherit the Y chromosome missing the SRY gene, resulting in XY females.

Question 23

What are balanced translocations?

Answer 23

The interchange of genetic material between nonhomologous chromosomes.

Question 24

What are balanced translocations?

Answer 24

Two chromosomes break and switch material that was broken. Usually no phenotype because no genetic material is lost. This individual can produce 6 different types of gametes. 2 gametes from alternate segregation where non homologous regions align and 4 gametes from adjacent segregation where portions of homologous sequences align

Karyotype example: 46, XX, t(3,6)(q13:q14)

Question 25

What cancers can result from reciprocal translocation?

Answer 25

Chronic myelogenous Leukemia (CML): translocation results in fusion protein w/ tyrosine kinase activity

Burkitt Lymphoma (solid tumor): c-myc oncogene (on chromosome 8) placed near Ig heavy chain locus activates Ig heavy chain gene which activates c-myc

Question 26

What is a Robertsonian Translocation?

Answer 26

Translocation of acrocentric autosomal chromosomes (13,14,15,21,22). Involves loss of short arms and fusion of two long arms at the centromere.

Individuals are normal because short arms contain redundant DNA but they do have one less chromosome (loss of two but gained one robertsonian)

Like reciprocal translocations, a carrier can produces 6 different gametes in two types through alternate segregation, and 6 possible conceptions if joined with normal gamete.

Conceptions that result in monosomy or trisomy are not compatible with life except one that results in trisomy 21 (causes 5% of down syndrome)

Question 27

What are deletions?

What are 2 clinical cases involving deletions?

What is a ring chromosome?

Answer 27

A type of chromosomal abnormality w/ loss of genetic material. Terminal deletions result in loss of the end of a chromosome. Interstitial deletions involve two breaks with loss of genetic material between the breaks.

1. cri‐du‐chat syndrome (“cry of the cat” in French) is caused by a deletion
   of the distal p arm of chromosome 5; the karyotype is 46, XY, del (5p).
2. Wolf‐Hirschhorn syndrome is caused by a deletion of the distal p arm of chromosome 4, 46, XX, del (4p).

Ring chromosomes result from breakage on both ends of a chromosome that then fuse. May arise following genetic damage or spontaneously during development. Results in monosomy of all daughter cells.

Question 28

What are microdeletions and three examples?

Answer 28

Small deletions that can be terminal or interstitial, usually affecting a large number of genes leading to microdeletion syndromes (aka contiguous gene syndrome).

Famous examples include:
Prader‐Willi (15q11‐13)
Angelman(15q11‐13)
DiGeorge (22q11.2)

Question 29

What are inversions?

Are they balanced rearrangements?

What is the affect on offspring?

Answer 29

A type of chromosomal abnormality where two breaks occur and the sequence in between is reinserted inverted.

If the inversion includes the centromere it is called a pericentric inversion

Inversions that do not include the centromere
are called paracentric inversions.

The arrangements are balanced so the parent is unaffected but their inverted chromosomes can’t align properly during meiosis 1 resulting in offspring with deletions or insertions

Question 30

What is genetic screening?

What are the 3 types?

Answer 30

“The search in a population for persons possessing
certain genotypes that (1) are already associated with
disease or predisposition to disease or (2) may lead to
disease in their descendants”

The three types are:

1. Population screening (includes newborn)
2. Prenatal screening
3. Family screening

Question 31

What are 3 diseases that all states require newborn screening for?

Answer 31

PKU, galactosemia and hypothyroidism

Question 32

What is medium chain acyl-CoA dehydrogenase deficiency (MCADD)?

What is the Biochemical Basis of MCAD deficiency?

How is it treated?

Answer 32

Autosomal recessive disease affecting metabolism 1/40 northern Europeans are carriers.

MCADD newborn screening is now required.

MCADD results in incomplete B-oxidation of fatty acids. Medium‐chain fatty acyl‐CoA can’t be broken down to Acetyl Coa, NADH or FADH2 resulting in decreased ATP, decreased ketogenesis, faster glycogen depletion and ultimately Hypoketotic hypoglycemia.

Treated with high carb diet and avoiding prolonged fast

Question 33

When is heterozygote screening used?

Answer 33

Heterozygote screening is used to detect unaffected carriers of disease causing agents w/in populations at risk for autosomal recessive disorders.

Used where prenatal diagnosis is available.

Tay-sachs screening is common w/ the Ashkenazi Jew population (1/30 are carriers). Some couples avoid birth of affected child by preimplantation genetic
diagnosis (PGD)

Question 34

What are two methods of prenatal screening?

Answer 34

Analysis of fetal tissue (amniocentesis, CVS, cordocentesis, in‐vitro fertilization diagnosis)

Visualization of the fetus (ultrasonography)

Question 35

When is Chorionic Villus Sampling (CVS) used?

Answer 35

9-12 weeks LMP to collect fetal trophoblastic tissue for cytogenetic and DNA testing.

Can detect chromosomal abnormalities and genotype

Question 36

When and What are Nuchal Translucency Ultrasound & Enzyme Tests used for?

Answer 36

They are used from 11-14 weeks LMP to check for neural tube defects or and risk of trisomies.

nuchal fold measurement (ultrasound) can detect neural tube defects

• *MSAFP** (maternal serum AFP):
• *High MSAFP = risk of neural tube defects**,
• *Low MSAFP levels = trisomies risk**

Question 37

When is amniocentesis used and what can it detect?

Answer 37

Amniocentesis is used 15-17 weeks LMP.

It is the collection of amniocytes and amniotic fluid for Cytogenetic analysis, DNA testing and Fetal AFP

• *High fetal AFP = high NTD risk**
• *Low fetal AFP levels = trisomies risk**

Question 38

What are two methods of maternal blood screening?

Answer 38

Triple screen: MSAFP, hCG, Estriol

Many false positives with triple screen.

Quadruple Screen: triple screen + Inhibin A (produced by placenta and ovaries, higher levels if fetus has down syndrome)
A quadruple screen increases the accuracy of down syndrome screening.