Chromosomal Abnormalities

Question 1

What is a chromosome?

Answer 1

A dense compaction of DNA, localised in the cell nucleus.

Question 2

How many chromosomes do healthy humans have in each cell?

Answer 2

46 (2n) in diploid (somatic cells), and 23 (n) in haploid (gametes).

Question 3

What is the prognosis for an embryo with a genetic abnormality?

Answer 3

Errors in the number or structure of chromosomes are generally not compatible with life. Where life remains, major diseases often result.

Question 4

What is Progeria? How is it caused?

Answer 4

Progeria is a genetic disease that causes premature aging (death around age 13). It is caused by a single base pair mutation in a gene involved in forming cell nuclei.

Question 5

What is hypertrichosis? How is it caused?

Answer 5

Hypertrichosis (werewolf syndrome) results in uncontrollable hair growth (otherwise healthy individuals). it is caused by a rearrangement of genes in chromosome 8.

Question 6

What is “Ploidy”?

Answer 6

Ploidy refers to the number of chromosomes in a cell - normal human gametes are haploid (n=23) and somatic cells are diploid (2n=46).

Question 7

What is Euploidy

Answer 7

It means the affected person has the correct number of chromosomes. Euploidic disorders would thus normally be structural, altering the chromosomes size or information.

Question 8

What is Aneuploidy

Answer 8

An absence of euploidy. With aneuploidy, the person does not have the correct number of chromosomes. They could have extra chromosomes (trisomy 21) or a missing chromosome (Turner’s Syndrome).

Question 9

What does it mean if a disease is -somy (e.g. trisomy, monosomy)

Answer 9

It means that the ‘error’ occurs in the duplication or deletion of one chromosome, and the other chromosomes are generally normal (e.g. trisomy 21, monosomy 7).

Question 10

Why is aneuploidy usually lethal in-utero

Answer 10

In addition to the abnormalities the chromosomal defect may cause, the sheer amount of material required to generate the nucleotides (or left as surplus from the missing material) disrupts equilibrium in the cells to the extent that it is not compatible with life.

Question 11

When is aneuploidy not lethal in-utero

Answer 11

When one of the smaller chromosomes is duplicated or missing (13, 14, 18, 21, x or y). As these do not require as many nucleotides as a large chromosome, the foetus may survive to birth.

Question 12

How common is Down Syndrome, and what are five symptoms

Answer 12

1:750 births.  It causes
Craniofacial defects
Cardiac defects
Cognitive impairment
Reduced Height
Reduced life expectancy
increased risk of Alzheimer's Disease
Lowered Fertility

Question 13

What is the primary risk factor for Down Syndrome?

Answer 13

Maternal Age, however there is a small correlation with paternal age.

Question 14

Briefly outline the three types of Down Syndrome

Answer 14

Trisomy 21 - occurs in 90-95% of cases, and results from a duplication of chromosome 21 in either sperm or egg.

Mosaic trisomy 21 - occurs in 2-3% of cases, with only some cells containing the trisomy. It is caused by abnormal cell division after fertilisation.

Translocation trisomy 21 - occurs in 4-5% of cases, where part of Chromosome 21 transfers to another chromosome (generally 13, 14, 15, or 22). The effected individual may have 46 chromosomes, but the genetic material of 47.

Question 15

Are chromosomal abnormalities common in human oocytes?

Answer 15

Yes - a study of IVF patients of advanced age found 61.8% of oocytes had an abnormality that could cause aneuploidy in the embryo.

Question 16

What is trisomy 18

Answer 16

Edwards Syndrome. It occurs in 1:6,000 births, with a very high mortality rate in-utero. It disrupts normal development and causes heart and kidney disorders.

Question 17

What is trisomy 13

Answer 17

Patau Syndrome. It affects 1:10,000 births, with a very high mortality rate (50% at one month). It often causes fusion of the nose and eye, as well as heart and kidney defects.

Question 18

What is the primary cause of aneuploidy? What does it result in?

Answer 18

Nondisjunction during meiosis.
If it occurs during Meiosis I, all gametes will be affected (2 n+1, 2 n-1).
If it occurs in meiosis II, only half the gametes will be affected (2 n, 1 n+1, 1 n-1).

Question 19

Why is aneuploidy in sex chromosomes tolerated better than in autosomes?

Answer 19

1. Females have x-inactivation, so only one X chromosome expresses its genes in a given cell - additional ones are unlikely to compete with each other.
2. The Y chromosome is small, if it is duplicated, cell equilibrium is not catastrophically affected.
3. Genes on the Y chromosome are not required for survival, so abnormalities are not generally catastrophic.

Question 20

What are the four sex chromosome disorders? Which are minor and which are major?

Answer 20

XXX and XYY are minor disorders, and do not always present a phenotype. Monosomy X (turner Syndrome) and XXY (Klinefelter Syndrome) are the more major disorders.

Question 21

What percentage of foetuses with chromosomal abnormalities survive to birth?

Answer 21

5% - almost exclusively with Down Syndrome.

Question 22

Describe Turner Syndrome

Answer 22

Monosomy X - caused by a missing X chromosome, or rarely, a rearranged second X chromosome. It only effects females, occurring in 1:2,500 births. Carriers can live a comparatively normal life, however it can cause short stature, sexual infantism, an minor or major physical abnormalities.

Question 23

Describe Klinefelter Syndrome

Answer 23

XXY - an additional X chromosome in males. It occurs in 1:500-1,000 births, and not all carriers develop symptoms. When they occur, symptoms include hypogonadism and increased stature. There is a highly debated link to increased criminality.

Question 24

What does it mean if a chromosomal rearrangement is ‘balanced’?

Answer 24

It is a homologous recombination (generally caused by chiasma crossover). Balanced rearrangements are omnipresent, and necessary for genetic diversity. They are referred to as balanced because they do not result in a net gain or loss of genetic material, and do not exhibit a phenotype.

Question 25

What does it mean if a chromosomal rearrangement is ‘unbalanced’?

Answer 25

There is a net gain or loss of genetic material, and a high chance of exhibiting a phenotype. The size of the rearrangement will often determine the consequences.

Question 26

What are the five basic forms of chromosomal rearrangement?

Answer 26

Deletion 
Duplication
Inversion 
Insertion
Translocation

Question 27

Describe ‘deletion’ as a form of chromosomal rearrangement. Give two examples of diseases it can cause

Answer 27

Loss of DNA sequence within a single chromosome - loss of genetic material.

Cri du Chat syndrome - deletion of 5p. It causes congenital malformation of the larynx, intellectual disability, delayed development and microcephaly

Prader-Willi and Angelman syndromes can be caused by deletion or non-expression of chromosome 15. They cause low muscle tones, short stature, incomplete sexual development, and behavioural problems including excessive eating.

Question 28

Describe Duplication as a form of chromosomal rearrangement.

Answer 28

Duplicated section within a single chromosome - gain of genetic material.

Question 29

Why do chromosomal duplications and deletions often occur together?

Answer 29

During meiosis, chiasma crossover often occurs to increase genetic variability. If there is a partial nondisjunction, one chromosome may come away with a duplicate of a particular section, leaving the other chromosome missing it altogether.

Question 30

Describe inversion as a form of chromosomal rearrangement

Answer 30

Inversion results in the reversal of a section of DNA within a single chromosome. This can occur when genetic material forms an ‘inversion loop,’ so rather than ABCDEF, CDE might form a loop, which when replicated would make it ABEDCF.
Inversions are balanced rearrangements, so may not result in a phenotype.

Question 31

Describe Insertion as a form of chromosomal rearrangements

Answer 31

A sequence of DNA is moved from one chromosome to another, leaving one chromosome shorter, and one longer, but not resulting in a net gain or loss of genetic material.

Question 32

Briefly describe chromosomal translocation and its two main sub-types.

Answer 32

Translocation occurs when sequences of DNA on two separate chromosomes are swapped with each other. This can cause many diseases, including many cancers. It can also be asymptomatic, resulting only in reduced fertility or zygote abnormalities if gametes are produced with insufficient or excess genetic information.

Reciprocal translocations are often asymptomatic and occur when the DNA is swapped, so that the new derivative chromosome carries DNA from both parts.

Robertsonian translocations are a distinct form of reciprocal translocation that results in a split at the centromere - the long arms of each chromosome combine, as do the short arms - leaving one very large and one very small chromosome which may be lost.

Question 33

Describe a Robertsonian translocation

Answer 33

The translocation occurs at the centromere, resulting in one chromosome with two q-arms, and one with two p-arms. It can only occur in the five acrocentric chromosme (13, 14, 15, 21, 22).

The short armed derivative chromosome is often lost, leaving the frequently asymptomatic carrier with 45 chromosomes.