Phenotypic variability

Question 1

What do we mean by environment?

Answer 1

External factors to the patient

Question 2

What is multiple endocrine neoplasma type 1?

Answer 2

Disease increases carriers chance of developing adenomas in endocrine tissue
Autosomal dominant

Question 3

What causes multiple endocrine neoplasma type 1?

Answer 3

Caused by a mutation in MEN1 gene- a tumour suppressor gene
Not all people develop the same type of adenoma or at the same time.
This is because a second event has to occur to promote tumour formation- clear environmental impact

Question 4

What is the affect of an individual’s sex on a disease?

Answer 4

Females have a number of physiological differences to males- these differences can affect the phenotype displayed by individuals with the same mutation
May be due to absence of organs/ tissues
e.g. men with BRCA-1 and BRCA2 gene have increased risk of prostate cancer- in females theres an increased risk of ovarian cancer

Question 5

How does hereditary haemochromatosis affect males and females differently?

Answer 5

In men symptoms begin to develop between 40- 60
In females symptoms begin after menopause
This is because females loose significant amount of blood during menstruation- prevents build up of excess iron
Men tend to have more sever phenotypes

Question 6

What is congenital long-QT syndrome?

Answer 6

Rare cardiac disorder caused by mutation in KCNQ1 and KCNH2

Can result in ventricular arrhythmia and thus sudden death

Question 7

How does congenital long-QT syndrome affect males and females differently?

Answer 7

Females more likely to be diagnosed with long QT syndrome possibly due to ascertainment bias- diagnostic criteria is based on females having longer QT on average

Studies show that females with long QT syndrome have higher risk of inheriting the mutation than males- may be due to positive selection of allele due to reproductive advantage

Question 8

What effect do other genes have on a disease?

Answer 8

Life course of a disease and symptoms is commonly modified by the presence of other genes
These genes can improve condition or make it work

Question 9

How is eye colour controlled by the effect of more than 1 gene?

Answer 9

You need both active HERC2 and active OCA-2 to have brown eyes
In addition to HERC2 theres over 16 genes that influence eye colour

Question 10

What are cystic fibrosis modifiers?

Answer 10

Theres a number of gene variations that interact with CF mutations to alter the phenotype:
Patients with homozygous delF508 mutation can be classified as having severe or mild lung disease
TGF-beta-1 (transforming growth factor B-1) variants are associated with phenotype for severe lung disease

Risk of developing CF can be modified by large number of gene variations:
e.g. immunoglobin FC-gamma receptor II (FCGR2A) can increase chance of developing chronic pseudomonas aeruginosa infection by fold 4

Question 11

What are von Hippel- Lindau syndrome modifiers?

Answer 11

VHL is a dominantly inherited cancer syndrome predisposing to a variety of malignant and benign neoplasms
Variation in cyclin D1 alters phenotype of VHL. number of individuals with retinal angiomas is higher in individuals with G allele compared to AA homozygotes
Possession of 1 or more G allele is associated with earlier diagnosis of CNS hemangioblastoma by almost 2 fold

Question 12

What causes Duchenne and Becker muscle dystrophy?

Answer 12

Mutation in dystrophin gene; largest known human gene

Question 13

How do Duchenne and Becker muscle dystrophy differ?

Answer 13

Becker muscular dystrophy is a more mild phenotype with age of onset around 12 years; some patients have no symptoms until later on in life
Loss of ambulation varies from adolescence onwards with death in 4th - 5th decade

Question 14

Why do Duchenne and Becker muscle dystrophy differ?

Answer 14

Both mutations are a result of deletion of the dystrophin gene but in DMD the mutation is a frameshift deletion, therefor no active dystrophin is produced
In BMD the mutation doesn’t result in a frameshift so active dystrophin is produced

Question 15

What are unstable mutations?

Answer 15

Theres a large group of diseases termed trinucleotide repeat disorders. Underlying cause is trinucleotide repeat expansion
Region where theres 3 repeated nucleotides expands during DNA replication

Question 16

How many repeats must there be in trinucleotide repeat disorders to cause instability?

Answer 16

Fewer than 27 repeats = stable and normal protein function
27-35 repeats= intermediate phenotype with minor affects
36-39 repeats = characteristic phenotype, not all carriers will be affected by disease
40< = disease
As number of repeats increases it reaches a threshold where its no longer stable
Greater the number of repeats, the more severe the phenotype

Question 17

What is an example of a trinucleotide repeat disorder?

Answer 17

Huntington disease

CAG repeat results in production of polyglutamine tract (poly Q tract)

Question 18

What causes 2 individuals to show different symptoms when they have the same mutation (same environment) ?

Answer 18

A second gene is modifying the disease phenotype

Monozygotic twins will be affected the same

Question 19

What is the likely cause of differences in severity of disease and age of onset in a family affected by a mitochondrial disease?

Answer 19

A variable number of mitochondria with the mutation are inherited

Question 20

What is likely cause of a genetic mutation causing a variety of diseases?

Answer 20

Different mutation in the same gene resulting in different diseases

Question 21

What is the likely cause of a genetic disease affecting no 2 people the same way?

Answer 21

Environmental factors modify the phenotype