Abnormalities of Chromosome Structure

Question 1

chromosomes that have their centromere near the middle are called what?

Answer 1

metacentric chromosomes

Question 2

chromosomes that have their centromere somewhat offset from the middle are called what?

Answer 2

submetacentric chromosomes

Question 3

T or F. Both metacentric and submetacentric chromosomes have critical “single-copy” genes along their lengths, on both the p and q arms

Answer 3

T

Question 4

What is an acrocentric chromosome?

Answer 4

Chromosomes with long (q) arms that contain critical “single-copy” genes (similar to other chromosomes), but also have short arms with specialized structures.

In the microscope, acrocentric short arms can be recognized by their characteristic appearance with “stalks” and “satellites”

Question 5

Which chromosome are acrocentric?

Answer 5

13, 14, 15, 21, 22

Question 6

What do acrocentric short arms consist of?

Answer 6

1) repetitive sequences (similar sequences that are present in many copies).
2) all of our rRNA genes

Question 7

What is the significance of the redundancy in rRNA gene copy number in acrocentric short arms?

Answer 7

a lot of variability is tolerated with absolutely no effect on phenotype

Question 8

What are two examples of highly redundant sequences that can be quite variable with no phenotypic consequences?

Answer 8

rDNA and “noncentromeric heterochromatin” (typically located just under/adjacent to the centromere

Question 9

Which are more common, number or structural chromosome abnormalities?

Answer 9

numerical

Although relatively rare compared to numerical abnormalities, structural abnormalities are an important category of genetic disorders.

Question 10

What is a balanced reciprocal translocation?

Answer 10

when two chromosomes exchange similar regions of their own chromosome with he other

Question 11

What is a paracentric inversion?

Answer 11

When segments on the same arm of a chromosome switch positions (translocate)

Question 12

What is a pericentric inversion?

Answer 12

When two segments on the same chromosome but not on the same arm exchange positions

Question 13

Will a person with a balanced karyotype be expected to have a normal phenotype? If so, why is it worth noting?

Answer 13

Yes, they will be normal but they have a risk of passing an unbalanced karyotype to their children

Question 14

What is different about an unbalanced karyotype from a balanced one?

Answer 14

an unbalanced karyotype (as a result of some type of structural abnormality) will have a net loss or gain or genetic material, while a balanced karyotype will not lose or gain genetic material during an exchange.

Unbalanced karyotypes have a high risk of showing phenotypic abnormality

Question 15

T or F. A reciprocal translocation involving the exchange of genetic material between two homologous chromosomes

Answer 15

F. It involves the exchange of genetic material between two NON-homologous chromosomes

Question 16

Why can reciprocal translocations only occur between two q arms?

Answer 16

It doesn’t. Reciprocal translocations are random and can occur on either arm and on any chromosome

Question 17

Are reciprocal translocations balanced or unbalanced?

Answer 17

Balanced. So the person who has it will be phenotypically normal, but they have risk of passing an unbalanced karyotype to offspring

Question 18

what does this indicate:

46,XY,t(2;15)

Answer 18

translation of chromosomes 2 and 15 on a male with 46 chromosomes

Question 19

What is a simple translocation?

Answer 19

a reciprocal translocation where one of the breakpoints is very near a telomere

Question 20

What is a Robertsonian translocation?

Answer 20

involves Long arm fusion of any two acrocentric chromosomes (i.e. the long arms fuse together and their associated short arms also fuse and are lost)

NOTE: the fused long-arm chromosome has a single functional centromere

Question 21

A balanced carrier of a Robertsonian translocation has a chromosome number of what?

Answer 21

45

Question 22

Why is a Robertsonian translocation considered balanced?

Answer 22

Besides all of the critical genes are located on the long arms so no genetic material is lost during the fusion

NOTE: the short arms consist entirely of redundant material, and the loss of this material is of no consequence

Question 23

T or F. A Robertsonian translocation can occur on chromosome 17

Answer 23

False. They can only occur on acrocentric chromosomes (i.e. 13, 14, 15, 21, and 22)

Question 24

what does this indicate:

45,XY,der(14;21)

Answer 24

Robertsonian translocation- remember that the two p arms of each chromosome is lost during the fusion of two q arms

Question 25

What is a Partial trisomy?

Answer 25

a structural abnormality that results in 3 copies of a particular chromosome segment

Question 26

What is a Partial monosomy?

Answer 26

structural abnormality resulting in only one copy of a chromosome segment

Question 27

T or F. Unbalanced structural abnormalities carry a high risk of abnormal phenotype

Answer 27

T

Question 28

What is the difference between and interstitial deletion and a terminal deletion?

Answer 28

Interstitial deletion involves two breaks on one arm and the loss of a segment & rejoining of broken arms

Terminal deletion involves a single break & loss of acentric terminal segment followed by the acquisition of new telomere (e.g. telomere healing)

In either case, deletion gives rise to a partial monosomy

Question 29

A condition where a person has one normal copy of chromosome 4 in addition to the one that is missing the tip of 4p would be called?

Answer 29

partial monosomy

NOTE: This particular abnormality is seen often enough to constitute a syndrome called Wolf-Hirschhorn syndrome

Question 30

partial trisomy is characterized by what?

Answer 30

A normal homolog and a homolog with two copies of a gene (added through a process called duplication)

Question 31

Would a duplication (resulting in partial trisomy) be considered a balanced or unbalanced structural abnormality?

Answer 31

unbalanced

Question 32

Are patients with chromosomal inversion (either paracentric or pericentric) considered balanced or unbalanced?

Answer 32

balanced (so they are phenotypically normal but carry reproductive risk- i.e. meiotic recombination within paired inversion loop may give rise to unbalanced gamete)

Question 33

What is a isochromosome abnormality?

Answer 33

arises when a centromere splits in the wrong direction during cell division, separating the two short arm chromatids from the two long arm chromatids (so there are still two chromosomes but one has two q arms and the other has two p arms)

NOTE: This is the only abnormality that does not involve incorrect repair of broken segments.

Question 34

Is an isochromosome abnormality balanced or unbalanced?

Answer 34

unbalanced

Question 35

Which is most likely to show phenotypic manifestation:

1) large imbalances
2) Robertsonian translocations
3) small duplication
4) inversion

Answer 35

Small duplication

Robertsonian translocations and inversions are balances and will not typically manifest phenotypically. Large imbalances will not be viable. Small duplications, on the other hand, are viable and will cause phenotypic issues (i.e. intellectual disability +/- developmental anomalies)

Question 36

T or F. Some types of unbalanced structural abnormalities (interstitial deletions, duplications) are less likely to be inherited and more likely to have arisen de novo in the patient

Answer 36

T

Question 37

What are some typical phenotypic consequences of unbalanced karyotypes?

Answer 37

Developmental delay (intellectual disability)

Growth delay

Facial dysmorphology & physical malformations

Congenital organ malformations, such as heart defects

Question 38

Typically, is monosomy or trisomy more severe?

Answer 38

monosomy

Question 39

T or F. Autosomal imbalance is less severe than sex chromosome imbalance

Answer 39

F. Sex chromosome imbalance is better tolerated (as long as viability requirements for the X chromosome are met)

Question 40

What is something that typically helps moderate the effects of chromosome abnormality, whether it is structural or number?

Answer 40

mosaicism

Question 41

What is the take-home message is that people who carry a balanced rearrangement?

Answer 41

They are expected to be phenotypically normal themselves, but they often are at risk to produce unbalanced gametes and, potentially, offspring with clinically significant problems.

NOTE: all types of balanced rearrangement carry reproductive risks

Question 42

Would someone who is 46,XY,t(8:9) be considered balanced or unbalanced?

Answer 42

balanced (reciprocal translocation)

Question 43

Notes on Nature of risk of Reciprocal Translocations

Answer 43

Incidence of balanced translocation carriers ~1 in 500-1000 (normal phenotype)
Often familial

Three categories of gametes produced:
Normal ® normal phenotype
Balanced ® normal phenotype
Abnormal / Unbalanced ® abnormal phenotype or miscarriage