Genetics

Question 1

What is gonadal mosaicism?

Answer 1

• Occurs when precursor germline cells to ova/sperm are a mixture of 2 or more genetically different cell lines (due to errors in mitosis).
• One cell line is normal and the other is mutated.

Question 2

What does mosaicism mean?

Answer 2

“Mosaicism” means a combination of cells.
Some have normal genes and chromosomes.
Some have mutated genes or chromosomes.
- If someone has germline mosaicism this means that some of their egg or sperm cells are normal and some contain a specific genetic mutation or chromosome problem.

Question 3

Is the parent affected by germline/gonadal mosaicism?

Answer 3

The parent is healthy as the genetic change is only in the germline so all other cells are unaffected (have the usual/normal genetic components) but the foetus may have genetic diseases.

Question 4

What increases the incidence of gonadal mosaicism?

Answer 4

• The incidence increases with advancing paternal age.

Question 5

Where is gonadal mosaicism commonly observed?

Answer 5

• More common in males.
• Can be observed with ANY inheritance pattern but most commonly autosomal dominant and X-linked.
• Observed in a number of conditions e.g. osteogenesis imperfecta and Duchenne’s muscular dystrophy.

Question 6

When is germline mosaicism usually confirmed?

Answer 6

Germline mosaicism is usually only confirmed if parents have more than one child with the
same genetic or chromosome disorder when both parents are not affected or carriers of
the condition.
N.B. Conditions that are inherited by means of germline mosaicism are often mistaken as being the result of de novo mutations (occurs for the first time in the family and not due to mutated genes/chromosomes in either parent).

Question 7

List 4 examples of diseases with genetic causes.

Answer 7

Genetic- individually rare but cumulatively enough to have regional genetic services:

1. Down’s Syndrome.
2. Cystic Fibrosis.
3. Huntington Disease.
4. Haemophilia.

Question 8

List 4 examples of diseases with multifactorial causes.

Answer 8

Multifactorial- main causes of diseases in devleoped countries:

1. Spina Bifida.
2. Cleft Lip/Palate.
3. Diabetes.
4. Schizophrenia.

Question 9

List 4 examples of diseases with environmental causes.

Answer 9

Environmental- main causes of disease in 3rd world and A&E (genetics can play a small role):

1. Poor diet.
2. Infections.
3. Drugs.
4. Accidents.

Question 10

What is autosomal dominant inheritance?

Answer 10

Only 1 copy of the mutant gene is required for the individual to be affected so the disease manifests in the heterozygous state.

• Males and females affected in equal proportions.
• Affected individuals in multiple generations.
• Transmission by individuals of both sexes to both sexes.

Question 11

For what reasons might both parents be unaffected (in relation to an autosomal dominant condition)?

Answer 11

3 main reasons:

1. Most commonly, they don’t have the genes for it due to gonadal mosaicism.
2. Sometimes the mother has reduced penetrance.
3. Sometimes the mother has variable expression i.e. the disease is there but not expressed clearly.

Question 12

What chance is there that an offspring inherits an autosomal dominant condition from 1 affected and 1 non-affected parent?

Answer 12

As only 1 defective gene is required, there is a 50% chance of offspring having the condition.

Question 13

What type of inheritance is responsible for male-to-male transmission?

Answer 13

The only way to pass on disease from male to male is by autosomal dominance inheritance- so if any male-to-male transmission seen, it is this form of inheritance.

Question 14

What is an example of autosomal dominant inheritance?

Answer 14

Huntington’s disease.

Question 15

What is autosomal recessive inheritance?

Answer 15

Both/2 copies of the mutant gene required for the individual to be affected so the disease manifests only in the homozygous recessive state.

• Males and females affected in equal proportions.
• Affected individuals only in a single generation.
• N.B. Recessive disorders most common in families where parents are related i.e. consanguineous.

Question 16

What chance is there that an offspring inherits an autosomal recessive condition from 2 carrier parents?

Answer 16

2 defective genes are required, so:

• 25% chance of offspring have the condition.
• 50% chance of offspring being carriers.
• N.B. Healthy siblings have 2/3 chance of being carriers.

Question 17

What is an example of autosomal recessive inheritance?

Answer 17

Cystic fibrosis.

Question 18

What is cystic fibrosis?

Answer 18

A chronic condition affecting mainly the lungs and the gut, variable presentation.

Question 19

What is the incidence of cystic fibrosis?

Answer 19

Incidence of 1 in 25,000.

N.B. The most common autosomal recessive condition affecting whites in the U.K.

Question 20

What is the population carrier frequency for cystic fibrosis?

Answer 20

1/25 i.e. 25% of the population are carriers.

N.B. If both parents are carriers, you have a 50% chance of being a carrier.

Question 21

How does the calculation vary when looking at probabilities for the risk of being a carrier?

Answer 21

The already affected child is disregarded- e.g. with the autosomal recessive condition, if you get:
- 1 unaffected offspring.
- 2 carrier offspring.
- 1 affected offspring.
The probability of being a carrier is not 1/2 as the affected individual is disregarded and the probability is actually 2/3.

Question 22

What is X-Linked A.K.A. Sex-Linked inheritance?

Answer 22

Caused by a mutation in genes on the X chromosome.

Question 23

What are examples of X-Linked inheritance?

Answer 23

Haemophilia and Duchenne’s muscular dystrophy.

Question 24

What scenario never involves X-Linked inheritance?

Answer 24

X-linked can never involve male-to-male transmissions so can never be passed from father to son.

• This is because sons always get their X chromosome from their mother.
• N.B. Males= XY, females= XX.

Question 25

How does X-Linked inheritance affect offspring?

Answer 25

• All offspring of affected male and unaffected (and non-carrier) female are unaffected.
• All daughters from an affected male are carriers (since they inherit the X) although sons would be unaffected (as long as the mother isn’t affected/a carrier).
• Males can never be carriers (either affected/unaffected).
• Transmission usually through unaffected females.

Question 26

What is an example of a condition inherited by X-Linked recessive inheritance?

Answer 26

Duchenne’s muscular dystrophy.

Question 27

What is an example of a condition inherited by X-Linked dominant inheritance?

Answer 27

Alport’s syndrome (kidneys).

Question 28

What is lyonisation?

Answer 28

The process of X chromosome inactivation.

• One of the 2 X chromosomes in every cell in a female is randomly inactivated early in embryonic development.
• The X chromosome is inactivated to prevent the female cells having twice as many gene products from the X chromosome as males.
• Only 1 functional copy of X chromosome.

Question 29

What is a Barr body?

Answer 29

The inactive X chromosome since packaged in heterochromatin (it cannot be transcripted).
- Small, densely staining structure in the cell nuclei of females, consisting of a condensed, inactive X chromosome

Question 30

What is imprinting?

Answer 30

For some genes, only 1 out of the 2 alleles is active and the other is inactive.
- For particular genes, it is always the paternal or the maternal allele.

Question 31

What is Knudson’s 2-Hit Hypothesis?

Answer 31

Gene mutations may either be inherited or acquired during a persons life.
Sporadic cancers= 2 acquired mutations.
Hereditary cancers= 1 inherited mutation + 1 acquired mutation.

Question 32

What is an ideogram?

Answer 32

The diagrammatic form of chromosome bands, bands are numbered accordingly to their distance to the centromere.

Question 33

How can genetic diseases be classified?

Answer 33

• Chromosomal.
• Mendelian- autosomal dominant/recessive or X-linked.
• Non-traditional- Mitochondrial (all mitochondria is inherited from the mother so males can’t pass on mitochondrial mutations), imprinting and mosaicism.

Question 34

What do the shapes in genetic pedigrees denote?

Answer 34

Square= male.
Circle= female.
Highlighted= affected.