Phenotypic Variability

Question 1

What is meant by phenotypic variability?

Answer 1

variation of gene expression in the same disease in different individuals, such that individuals with the same genetic disease may not have the same symptoms or presentations

Question 2

What is the difference and similarities between osteogenesis imperfecta subclasses?

Answer 2

they all result in fragile bones prone to fracture, but they have different disease outcomes, inheritance patterns and underlying causes

Question 3

What are the 5 reasons as to why phenotypic variablity exists? MUMES

Answer 3

Mutations
Unstable
Modifiers
Environment
Sex

Question 4

What is meant by modifiers?

Answer 4

When the expression of one gene directly affects the presence of other genes

Question 5

How is the life course of a disease and its symptoms modified?

Answer 5

modified by the presence of other gene variants, these genes can improve the condition or make it worse

Question 6

What and How is eye colour affected?

Answer 6

It is an autosomal dominant trait
There are a number of other genes which interact with OCA-2 and can alter eye colour
OCA-2 you inherit is responsible for approximately 80% of eye colour (ther rest by other genes)
The second most important gene is HERC2
This controls the activity of OCA-2

So even if you inherit active form of OCA-2 you will have blue eyes if you have the inactive form of HERC-2

Question 7

How many genes affect eye colour?

Answer 7

16 other genes

Question 8

What is meant by the effects of mutations on the phenotype of a disease?

Answer 8

Different subtypes of the same disease have different presentations, due to mutations within the same gene

Question 9

What is the most simple way the effect of an individual sex has on a disease?

Answer 9

The presence or absence of organs

Question 10

Give an example how presence/ absence of organs in an individual’s sex has an effect on a disease?

Answer 10

men with mutations in BRCA-1 and BRCA2 have an increased risk of prostate cancer, this is obviously not the case with females as they lack a prostate instead they have an increased risk of ovarian cancer

• men will still have an increased risk of breast cancer with this mutation, though it is not as high as in women

Question 11

What is an example of how sex affects the phenotype of a disease?

Answer 11

In hereditary haemochromatosis - women lose blood through menstruation and therefore generally have lower iron levels

Question 12

What is congenital long-QT syndrome?

Answer 12

Group of rare cardiac disorders characterised by a prolonged QT interval
They can result in syncope (fainting/ passing out), ventricular arrhythmias, and thus sudden death
The most common subtypes or LQT1 and LQT2
These are caused by mutations in KCNQ1 and KCNH2 respectively
Both are inherited in an autosomal dominant fashion

Question 13

What is the LQT1 AND LQT2 sex bias?

Answer 13

Females are more likely to be diagnosed with long QT syndrome generally, possibly due to ascertainment bias- since the diagnosis criteria is based on QTc and females on average have a longer QTc

Females are also more likely to inherit the condition and to pass it on than fathers

Females that inherit it are all most likely to show symptoms (when they are older and more likely to be non-fatal), but not usually men (fatal and younger)

After puberty women are more likely to experience fatal cardiac events and rate of cardiac events in males drop

Question 14

What is an example of how mutations affect the phenotype of a disease?

Answer 14

Duchenne vs Becker muscular dystrophy - slightly different mutations of the same gene cause different presentations

Question 15

What is the reason for the differences between Duchenne and Becker muscular dystrophy?

Answer 15

Both are the result of deletions in the dystrophin gene, but in DMD the mutation is a frameshift deletion and therefore no active dystrophin is produced

In Becker the mutation does not result in a frame shit and so active dystrophin is produced, although it is not the full length protein it retains some of the activity of the longer form

Question 16

What is an example of how modifiers affect the phenotype of a disease?

Answer 16

In CF, the variety of genes present can increase the degree of CF
They change the phenotype of the disease

Question 17

What is the CF lung disease cycle order?

Answer 17

-> Inflammatory response –> infectious response –> pharmacogenetic response –> ion channels –> cytoskeleton –> tissue damage and repair -

Question 18

What genes are associated with the phenotype of severe lung disease?

Answer 18

TGFB1, the gene encoding transforming growth factor beta-1

Question 19

What is Von-Hippel-Lindau Syndrome; VHL modifiers?

Answer 19

VHL is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms

Most frequent retinal, spinal hemangioblastoma, renal cell carcinoma, pheochromocytoma and pancreatic tumours

Question 20

What alters the phenotype of VHL?

Answer 20

variation in cyclin D1 (CCND1)

The number of retinal angiomas is significantly higher in individuals harbouring the G allele compared with AA homozygotes

Possession of 1 or more G alleles is associated with earlier diagnosis of CNS hemangioblastoma by almost 2 fold

Question 21

What are trinucleotide repeat disorders?

Answer 21

Where an increased number of nucleotide repeats (>27) cause more severe phenotypes throughout generations

Question 22

What affect do trinucleotide repeats have on the proteins produced?

Answer 22

Changes protein function

Question 23

What does a larger number of trinucleotide repeats result in?

Answer 23

More severe phenotype and earlier onset of disease

Question 24

If you have less than how many TNR’s is the mutation considered stable?

Answer 24

Less than 27

Question 25

If individuals are identical, and there is variation in the phenotype, what is likely to have caused the variation?

Answer 25

The environment

Question 26

In non-identical individuals with the same mutation, what could cause the variation in phenotype?

Answer 26

The presence of other genes as well as the environment

Question 27

In unrelated individuals, how does phenotypic variability arise?

Answer 27

Due to unstable mutations like TNRs

Question 28

If there is a binary presentation of a condition eg half a family have a condition and half don’t, what is likely to cause the variation?

Answer 28

The presence of a second gene modifying the disease phenotype

Question 29

If there are two forms of the same disease, and one is a milder phenotype, what is likely to cause the variation?

Answer 29

Mutations - Different mutations of the same gene results in different diseases

Question 30

When there is wide variation in a condition but the variation does not apply to monozygotic twins, what is likely to be causing the variation?

Answer 30

A second gene which the twins did not inherit

Question 31

When there is marked variability and no two members being affected in the same way, what is likely to cause the variation?

Answer 31

Environment

Question 32

What is Multiple endocrine neoplasia type 1 (MEN1)?

Answer 32

Disease which increases the carriers’ chance of developing adenomas in endocrine tissues
It is caused by a mutation in the MEn1 gene, a tumour suppressor gene

Question 33

How is MEN1 inherited?

Answer 33

Autosomal dominant fashion, but despite this not all people with the mutation will develop the same types of adenomas or when they are the same age
- this is because a second event has to occur to promote tumour formation
- therefore there is an environmental impact on the course of the disease

Question 34

What is Hereditary haemochromatosis?

Answer 34

This is an autosomal recessive disease
It is caused by a mutation in the human homeostatic iron regulator protein (HFE)
This affects the way in which dietary iron is absorbed leading to excess iron absorption
Leading to a buildup of iron in various organs and subsequent organ damage

Question 35

Do all patients with Hereditary haemochromatosis have clinically relevant iron accumulation?

Answer 35

No, only 10%
The dietary load of iron can vary considerably and lower levels of intake are associated with improved disease diagnosis

Question 36

When there is a large difference in the age of onset between family members, what is likely to cause this variation?

Answer 36

Unstable mutations

Question 37

What does the patient’s experience of sickle cell disease depend on?

Answer 37

the environment
e.g., airborne pollution

Question 38

What cause of variation is more likely to have transgenerational effects?

Answer 38

The expansion of unstable trinucleotide repeats

Question 39

What are muscular dystrophies?

Answer 39

Group of diseases which cause progressive wesakenss and muscle breakdown

Question 40

What is the most common type of muscular dystrophy?

Answer 40

Duchenne muscular dystrophy (50% of all cases)

Question 41

What is aetiology?

Answer 41

The cause of a disease or condition

Question 42

Does the gene affected vary in muscular dystrophy?

Answer 42

Yes

Question 43

What do all of the genes affected in muscular dystrophy have in common?

Answer 43

Attach to dystrophin through the cell membrane to the collagen in the ECM either directly or in the post translational modification of the proteins involved

Question 44

If individuals are genetically identical, what is the underlying cause of variation in the phenotype?

Answer 44

environmental

Question 45

What is the reason for variation if it is in non-identical individuals with the same mutation (e.g., family members)?

Answer 45

environmental interactions or the existence of variation in other genes which interact with the disease-causing mutation

Question 46

In unrelated individuals what is the cause of variation?

Answer 46

Different mutations, different disease-causing genes, unstable mutations in trinucleotide repeat disease (resulting in an increased severity of disease )

Question 47

What are non-genetic factors affecting CF?

Answer 47

environmental (air pollution, tobacco, increased infection risk, climate)

Socio-economic status

Access to healthcare

Adherence to treatment

Question 48

What are genetic factors affecting CF?

Answer 48

Candidate gene approach

Genome wide association studies

Whole exome sequencing