Disorders of Chromosome organization, Cytogenetics

Question 1

What is cytogenetics?

Answer 1

the study of chromosomes and their structures and variations in their structures

Question 2

Chromosomes hold all of our DNA. They are very complex. How is the DNA strand compacted to fit into a cell?

Answer 2

Each chromosome made up of a single, continuous DNA
double helix.
Chromosomes organized as chromatin a complex of 5 types of histones (basic proteins) plus heterogenous non- histone proteins and DNA.
DNA wrapped around the histone protein complexes.
›DNA-histone complex is called a nucleosome. Nucleosomes are arranged like beads on a string.
Each core nucleosome + spacer contains about 200
base pairs of DNA.

Question 3

What are the different ways you can stain chromosomes? What is the most common method?

Answer 3

G-banding Giemsa is the most common.

• Dark regions are heterochromatic and AT-rich
• Light regions are euchromatic and GC-rich

C-banding focuses on the centromere of the chromosomes.

R-banding reverse is the opposite of the G-banding.

Question 4

The Q and P arms of a chromosome represent what?

Answer 4

P arms= short arms

Q arms= long arms

Question 5

What are acrocentric chromosomes and what are the examples of them?

Answer 5

Chromosomes without P arms (short arms)

Chromosome 13, 14, 15, 21, 22 are example

Question 6

What are acrocentric chromosomes and what are the examples of them?

Answer 6

Chromosomes without significant P arms (short arms)

Chromosome 13, 14, 15, 21, 22 are example

Question 7

What does 1q31 and 8p23 denote?

Answer 7

They denote genes that are on chromosome 1, short arm at location “three one” not 31. Gene is on chromosome 8, long arm, at location “two three”.

Question 8

What is the difference between meiosis and mitosis?

Answer 8

Mitosis occur in somatic cells with production of identical daughter cells.
Meiosis occurs in germ cells with four daughter cells that are haploid. This is the process that leads to your gametes.

Question 9

If nondisjunction occurs in meiosis I, none of the daughter cells are normal. True of false?

Answer 9

True!!

If nondisjunction occurs in meiosis II, then only 2 daughter cells are normal.

Question 10

There are some genes that are expressed ONLY if they are inherited maternally OR paternally. What is this called?

Answer 10

Imprinting is normal.

Genomic imprinting is an epigenetic phenomenon that causes genes to be expressed in a parent-of-origin-specific manner.

Question 11

Pseudoautosomal regions (PAR) of human X and Y chromosomes are located on both ends of the X and Y chromosome. PAR 1 and PAR 2 are located specifically where on the sex chromosomes?

Answer 11

The pseudoautosomal regions (PAR1 and PAR2) of the human X and Y chromosomes pair and recombine during meiosis. Thus genes in this region are not inherited in a strictly sex-linked fashion. PAR1 is located at the terminal region of the short arms and PAR2 at the tips of the long arms of these chromosomes.

Question 12

What is lyonization?

Answer 12

X-inactivation (also called lyonization) is a process by which one of the copies of the X chromosome present in female mammals is inactivated. The inactive X chromosome is silenced by it being packaged in such a way that it has a transcriptionally inactive structure called heterochromatin

Question 13

About 50% of miscarriage or spontaneous abortion are due to this?

Answer 13

aneuploidy

Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes.

Question 14

There is a higher probability of nondisjunction in women with increasing age. True or false?

Answer 14

True

in the continued formation of our egg there is a higher chance of nondisjunction

Question 15

The likelihood of there being trisomy at the various stages of pregnancies decreases as the pregnancy continues. Why?

Answer 15

there is an increased risk of miscarriages

Question 16

What is the difference between triploidy and trisomy?

Answer 16

polyploidy: variation in # chromosome sets
aneuploidy: differences in chromosome number (not sets of chromosomes)

Question 17

Diandry is the most common form of triploidy where two sperm fertilize one normal ovum. This may be due to genetically determined weakness of what?

Answer 17

zona pellucida which is responsible for regulating interactions between ovulated eggs and free-swimming sperm during and following fertilization (prevent another sperm from attaching an ovum that has already attached to a sperm)

Question 18

Which describes the rare occurrence of a diploid sperm (complete nondisjunction during spermatogenesis) fertilizing an egg to form a partial hydatidiform mole?

Answer 18

diandry ( a triploidy)

partial hydatidiform mole: chorionic villi of placenta degenerate and form fluid-filled sacs; placenta is large; usually aborted in the first trimester

Question 19

Syndactyly of third and fourth fingers are classic presentation of what triploidy due to normal sperm fertilizing a binucleate diploid oocyte?

Answer 19

digyny

Question 20

A complete mole exists when the male chromosome complement doubles in the female ovum in effort to salvage the fertilization due to no female chromosome complement. This fertilization results in? What type of rescue occured?

Answer 20

complete paternal uniparental disomy
monosomy rescue

More commonly due to doubling of haploid sperm at fertilization of anucleate egg

uniparental disomy occurs when both copies of a chromosome are inherited from the same parent

Question 21

There are three forms of nondisjunction: failure of a pair of homologous chromosomes to separate in meiosis I, failure of sister chromatids to separate during meiosis II, and failure of sister chromatids to separate during mitosis. Nondisjunction results in daughter cells with abnormal chromosome numbers termed?

Answer 21

aneuploidy

Question 22

What is the difference between complete and partial mole?

Answer 22

Moles are an abnormal product of conception in which the chorionic villi are hydropic and hypoplastic and have a predilection to become malignant. There are two types of moles, complete and partial. Complete moles have no fetal development or no villi, whereas in partial moles, there is fetal development, but the villi are abnormal. The chromosomal complement in complete moles is 46,XX with the entire complement of androgenic origin. Partial moles are triploid (69 chromosomes) with two of the three complements paternal in origin.

Question 23

X-inactivation does not affect the whole chromosome. Inactivation is________, but the effect is permanent in all resulting daughter cells

› # X’s = Barr bodies + 1

Answer 23

random

Question 24

Expression of X-linked recessive diseases such as › DMD and hemophilia A in females are usually milder to due this genetic process. This process is also responsible for females having higher expression levels of steroid sulfatase.

Answer 24

lyonization AKA X-inactivation

Effects of lyonization:
›-Dosage compensation
›-A few genes on X escape inactivation
› Pseudoautosomal region
› A few genes outside the PAR are similar, but do not participate in crossing over
-A few genes outside of PAR that do not have a similar copy on the Y and therefore females have higher expression levels
› Steroid sulfatase

Question 25

In some cells, its our paternal X being expressed and in other cells its our maternal X being expressed. True or false?

Answer 25

True!

Question 26

Even though the risk of down syndrome per age is higher, only 9-10% of all pregnancies happen in women over 35%. So there’s so many more women under 35 having children that the opportunity for down syndrome to occur from pregnancies is that much more.

Answer 26

Thus a 20 year old female can have a child with down syndrome. It is not uncommon.

Question 27

What is the most common aneuploidy with epicanthic folds in eyes are a common characteristic phenotype and individuals affected can grow well into adulthood?

Answer 27

trisomy 21 AKA down syndrome

Question 28

What is the classic presentation of trisomy 18, Edward’s syndrome, 47,XY,+18?
This trisomy, 95% of the time is lethal.

Answer 28

Low BW, closed fist with index finger overlapping the 3rd digit and 5th overlapping the 4th

Question 29

This trisomy is associated with midline abnormalities such as a cleft lip/palate, holoprosencephaly and flexed fingers with polydactyly. It is considered more lethal than Edward’s syndrome.

Answer 29

trisomy 13, Patau Syndrome, 47, XY, +13

Question 30

Remember than chromosomes are numbered in order of decreasing size. So how does this correlate with trisomy 13 being worse than trisomy 18 or 21?

Answer 30

Trisomy 13 is a bigger chromosome so it has more genes causing more problems.

13>18>21 in reference to size
13>18>21 in reference to severity

Question 31

Significant edema of the female baby (cystic hygroma at the back of the head) at birth is characteristic of this monosomy.This is considered the only monosomy that is viable and is primarily due to paternal non-disjunction. What is this monosomy?

Answer 31

Turner’s syndrome
-females with only one X chromosome

The ovum was normal but the sperm did not have an X or Y chromosome inside. So the girl is just left with her mom’s X. This is NOT associated with advanced maternal age.

Question 32

This trisomy occurs in 1/1000 females. It is not associated with obvious physical abnormal phenotype, but female with it are generally tall.› Many undiagnosed, while others usually diagnosed in infertility clinics. About 70% have some learning problems. Its nondisjunction occurs in maternal meiosis I. Female have a normal life expectancy.

Answer 32

trisomy X, 47, XXX

Question 33

Klinefelter syndrome is what kind of trisomy? What are some typical characteristics?

Answer 33

47, XXY

-Hypogonadism
›-gynecomastia
›-Underdeveloped during puberty
›-Variable learning problems, can have poor psychosocial development
›-Usually infertile due to failed germ cell development; azoospermia

Half due to paternal meiosis I, others due to maternal meiosis I

Question 34

› 1/1000 male births – due to abnormal paternal meiosis II
› Not associated with obvious abnormal phenotype, are generally tall
› Attention deficits, hyperactivity, impulsiveness are common
› Generally normal intelligence, but speech and other therapies may be needed
› Normal fertility
› Reports in 1960s and 1970s led many to believe that it was associated with criminal behavior and psychopathology; very biased studies and this is now known not to be true

What is this aneuploidy?

Answer 34

47, XYY

Question 35

This syndrome can cause heart defects, poor immune system function, a cleft palate, and low levels of calcium in the blood. It is also known as velocardiofacial syndrome or 46, XX, del(22) (q11.21-q11.23) or 22q11 deletion.

Answer 35

DiGeorge Syndrome

Question 36

This syndrome has a 5p14 deletion associated “cry of the the cat” in newborns. Characteristics include low birth weight, microcephaly, hypertelorism, epicanthal folds, low set ears, micrognathia, and severe mental disability. Also known as 46, XY, del(5) (p14.2).

Answer 36

Cri du Chat syndrome

Question 37

What is genetic imprinting?

Answer 37

the differential expression of genes depending on the parent of origin
-the mechanism of inactivation or genomic imprinting involves DNA methylation of cytosine nucleotides

Question 38

This syndrome is caused by chromosomal 15q11 deletion derived from the father. Symptoms include failure to thrive at birth, hypotonia, veracious appetite in early childhood, obesity, small hands and feet, hypogonadism, and mental disability.

Answer 38

Prader-Willi Syndrome

Question 39

This syndrome is caused by chromosomal 15q11-13 deletion derived from the father. Symptoms include failure to thrive at birth, hypotonia, veracious appetite in early childhood, obesity, small hands and feet, hypogonadism, and mental disability.

Answer 39

Prader-Willi Syndrome

Question 40

What are the classical symptoms of Angelman syndrome and what chromosomal deletion does it involve?

Answer 40

chromosomal 15q11-13 deletion derived from the mother

• “happy puppet syndrome”
• gait ataxia
• short stature
• severe mental disability
• spasticity
• seizures

Question 41

Dup17p12 has the classical presentation of the foot drop. It is a progressive neurological disorder and affects peripheral nerves and results in loss of sensation and wasting (atrophy) of muscles in the feet, legs, and hands. What is the name of this syndrome?

Answer 41

Charcot-Marie Tooth

46, XY, dup (17) (p12)

Question 42

A male newborn arrives in the NICU to a 36 y.o. woman. The baby has a holoprosencephaly, ventricular septal defect, cleft palate, polydacyly, and is hypotonic with a poor suck. Karyotype is ordered. The most likely result is which of the following?

46, XY
46, XY, +13, der(13;14)(p10;p10)
47, XXY
47, XY, +13
47,XY,i(12p)

Answer 42

47, XY, +13

trisomy 13, Edward’s syndrome

Question 43

Risk for abnormal viable offspring is _______for pericentric carriers than paracentric.

Answer 43

higher

Question 44

Horizontal inheritance is a loose term, but essentially means every generation is not affected, and often only one is (hence, horizontal). Don’t get thrown off by the fact that the person in generation one is affected.

Answer 44

The goal is for you to identify that it is unlikely that two generations would go unaffected if it were autosomal or X-linked dominant (unless there was reduced penetrance or variable expressivity, phenomena that are typically avoided in the idealized pedigrees that you would be given in these types of questions). X-linked recessive and mitochondrial are very unlikely, which leaves you with autosomal recessive.

Question 45

Chromosomal rearrangements in which a segment of a chromosome is reversed end to end. What is this called when this rearrangement is within the same arm and when it is between two different arms of the same chromosome.

Answer 45

Paracentric (does not involve the chromosome)

Pericentric (involves the chromosome)

Question 46

During meiosis, homologous chromosomes, sister chromatids want to match their loci. In order for this to happen when an inversion has occurred, the chromatids have to twist and turn to get the homologous areas next to one another.

Answer 46

An individual with a pericentric inversion has a possibility 5-10% to have abnormal offspring.

An individual with a paracentric inversion has a very small chance of abnormal offspring (the dicentric and acentric chromosomes wouldn’t even survive or become viable).

Question 47

A couple with paracentric inversion will experience what as opposed to a couple with pericentric?

Answer 47

multiple miscarriages but once they have a successful birth the child is more likely to be normal than a child born to a couple with pericentric inversions

Question 48

Pallister Killian syndrome is due to what kind of chromosomal abnormality?

Answer 48

i(12p)= isochromosome 12p

isochromosome: chromosome with two identical arms, either p or q

extremely weak muscle tone (hypotonia) in infancy and early childhood
intellectual disability
distinctive facial features and sparse hair
areas of unusual skin pigmentation
47,XY,i(12p)

Patients with PKS have mosaïcism for a supernumerary isochromosome 12p, resulting in four copies of the short arm of chromosome 12 instead of the normal two. The isochromosome is mostly of maternal origin. Selection against i(12p) cells is observedin vitro, and probably also occurin vivo. Karyotype is 47, XX or XY, i(12)(p10)/ 46,XX or XY.

Question 49

What is the syndrome for isochromosome Xq [45,+i(Xq)]?

Answer 49

Turner’s syndrome
this type is found in 20% of females

A chromosomal disorder in which a female is born with only one X chromosome.

Question 50

A 4 week old male newborn was found to be positive for cystic fibrosis by Immunoreactive trypsinogen (IRT) and further DNA analysis showed two mutation withing the cystic fibrosis gene (CFTR). The parents are confused about how this occured because their 3 year old child is not affected. Which of the following is the most likely explanation?

Answer 50

Mendelian gene segregation

Question 51

A 9 month old boy is brought to the physician because of chronic dry cough lasting for 3 weeks and failure to thrive. His stools are frequent, bulky, and greasy. A quantitative sweat test result shows an elevated chloride concentration of 84 mEq/L. What is the likely mode of inheritance?

Answer 51

Cystic fibrosis which is autosomal recessive

Question 52

Pattern baldness is due to what mode of inheritance?

Answer 52

autosomal sex-influenced

Question 53

Which characteristics may be associated with autosomal recessive inheritance in humans?

Answer 53

consanguinity

Question 54

Vitamin D resistant rickets is due to what mode of inheritance?

Answer 54

X-linked dominant

Question 55

What does 46,XX,t(10;11)(p15;q21) mean?

Answer 55

This is a female (denoted by XX) with 46 chromosomes. There is a translocation that occurs where q21 of chromosome 11 breaks and p15 of chromosome 10 breaks and they both switch.

So 11q21 is now where 10p15 used to be. 10p15 is now where 11q21 used to be.

This shows a balanced reciprocal translocation carrier.

There is no loss of genetic material.

Question 56

› t(9;22)(q34;q11) denotes leads to the Philadelphia chromosome which is? What does this chromosome cause?

Answer 56

Philadelphia chromosome is the changed chromosome 22. So 9q34 is now in chromosome 22 where 22q11 used be. This changed chromosome 22 is longer. The ABL is moved next to the BCR promotor in chromosome 22. This results in ABL protein which is more active than normal.
ABL is a tyrosine kinase and its enhanced activity leads to the activation of oncogenes promoting chronic myelogenous leukemia.
9–> ABL
22–> BCR

Question 57

› t(8;14)(q24;q32) leads to the activation of what proto-oncogene to cause Burkitt’s lymphoma?

“B cell tumor of the jaw”

Answer 57

MYC- proto-oncogene 8q24

14q32 is where the immunoglobulin heavy chain locus is

they switch spots and now MYC has increased unregulated expression of myc.

Remember Ig are continuously produced by plasma (B cells).

Question 58

What is a Robertsonian translocation? What is the most common one found in man?

Answer 58

translocation between two chromosomes that are each acrocentric (no significant p arm but has a satellite DNA)

rob(13q14q)

Question 59

46,XY,der(14;21)(q10;q10),+21 is what kind of translocation and can cause what syndrome?

Answer 59

Robertsonian translocation. Chromosome 13, 14, 15, 21, 22 are the acrocentric chromosomes.

Down syndrome: Extra 21 chromosome (trisomy21)

Question 60

45,XY, rob(14;21) (q10;q10) is a balanced translocation carrier and causes no disease.

Answer 60

The other 21 chromosome (acrocentric) has attached to the top of chromosome 14. So you have 45 chromosomes.
No genetic component is lost and so the male appears normal phenotypically.

Question 61

Ring chromosomes are formed when breaks occur somewhere on either side of the centromere. The newly created fragments (and thus the genes on them) are lost and the remaining pieces of the short and long arms join with each, forming a ring. Ring chromosomes are unstable and tend to be lost during mitosis, creating a mosaic cell line. A ring chromosome X is found in ≈15% of individuals with this syndrome.

Answer 61

Turner’s syndrome

Question 62

1p, 5p, 7q, 8q, 9p, 10p, 20p, and 20q engage in what kind of chromosomal abnormality?

Answer 62

ring chromosomes

-Structurally abnormal chromosome in which the telomere of each chromosome arm has been deleted and the broken arms have joined

Question 63

What are marker chromosomes?

Answer 63

Sometimes there’s just random pieces of chromosome in a cell.
-For a long time we had a hard time identifying what “mar” belonged to, but now there are molecular techniques that make it easier
-Marker chromosomes can involve expressed genes that will then have a significant phenotype, but sometimes they can involve unexpressed or not expressed portions of the genome, which will
not have a significant phenotype
-The risk could be 0-100% (not sure what to tell pregnant woman)

Question 64

What is the genetic term for two or more chromosome complements in same person?

These are things that can change that phenotype.

Answer 64

Mosaicism:

When she says mosaicism, she means that there are 2 separate cell lines that are occurring in this person

If she took a skin sample and grew it, some of the cells would have an extra 21
chromosome and some cells wouldn’t have an extra 21 chromosome
▪ Note the 47, XX, +21 cell line may still be present
This could happen if maybe the pregnancy started as Down Syndrome with an extra 21,
but one figured out that it shouldn’t have an extra and did trisomic rescue and kicked
one of those chromosomes out, and that cell then went on to proliferate a normal cell
line that may have UPD, but it’s a normal cell line.

○ Generally the symptoms will be milder than if there is only a 47, XX, +21 cell line

Question 65

Chromosomes in Group D and G are what kind of chromosomes? What about groups A and B?

Answer 65

Group A: metacentric (1,2,3)
Group B: submetacentric (4,5)
Group D and G: acrocentric (13,14,15,21,22)

Question 66

47,XX,+i(5p)

Answer 66

Female with the regular chromosome compliment and an additional chromosome which is composed of two chromosome 5 short arms attached to each other

Question 67

46,XY,inv(7)(p14.2q36.3)

Answer 67

Male with a pericentric inversion on chromosome 7 from the short arm at
region 14.2 to the long arm at region 36.3. The centromere is involved.

Only one chromosome involved.

Question 68

46,XY,dup(15)(q26-qter)

Answer 68

Male with duplication involving the region between q26 and the end of the q arm of
chromosome 15

Question 69

What is a characteristic of the B-cell malignancies Burkitt’s lymphoma and acute lymphoblastic leukaemia (ALL)?

Answer 69

The reciprocal chromosome translocation, t(8;14), involving the heavy chain locus on chromosome 14 and the c-myc oncogene on chromosome 8