Phenotypic Variability

Question 1

What are genetic and environment interaction?

Answer 1

-Underlying causes of disease are genetic important role for environment (e.g. factors external to the patient) in progress and outcome of the disease for each patient

Question 2

What is Multiple Endocrine Neoplasia type 1 (MEN1)

Answer 2

-This is a disease which increases the carriers’ chance of developing adenomas in endocrine tissue

Question 3

What causes MEN1?

Answer 3

-Caused by a mutation in the MEN1 gene, a tumour suppressor gene

Question 4

How is MEN1 inherited? What is it impacted by?

Answer 4

• Condition inherited in an autosomally dominant
• Not all people with the mutation will develop the same types of adenoma or at the same time as a second event needs to happen to promote tumour formation so some develop many tumours at young age and others do not develop any tumours until v late in life

Question 5

What is Hereditary haemochromatosis?

Answer 5

-This is an autosomally recessive gene

Question 6

What is Hereditary haemochromatosis caused by?

Answer 6

-Caused by a mutation in the human homeostatic iron regulator protein (HFE)

Question 7

What are the impacts of Hereditary haemochromatosis?

Answer 7

• This affects the way in which dietary iron is absorbed leading to excess iron absorption
• This can lead to a build up of iron in various organs and subsequent organ damage.

Question 8

What are the different types of Hereditary haemochromatosis

Answer 8

• However only 10% of people with hereditary haemochromatosis have clinically relevant iron accumulation. Women are protected from iron accumulation due to menstrual bleeding. in men, the dietary load of iron can vary considerably and lower levels of intake are associated with improved disease prognosis.
• The natural history of many other diseases are affected by environmental factors for example cystic fibrosis and sickle cell disease can both be exacerbated by exposure to pollution

Question 9

What are other genes and disease progression ?

Answer 9

• In addition to the presence of the disease gene the life course of a disease and the symptoms present are commonly modified by the presence of other genes
• These genes can either improve the condition or make the condition worse.

Question 10

What are cystic fibrosis modifiers?

Answer 10

• number of gene variations that interact with the cystic fibrosis mutation to change the phenotype of the disease
• Variability of pulmonary phenotype and survival in cystic fibrosis, even among patients who are homozygous for the most prevalent mutation, delF508
• Variants of genes can modifiy cystic fibrosis

Question 11

What are examples of cystic fibrosis modifiers?

Answer 11

• Patients withe the same homozygous delF508 mutation can be clasified as having either severe or mild lung disease.
• TGFB1, the gene encoding transforming growth factor beta-1, variants are associted with with the phenotype of severe lung disease.

Question 12

What is FCGR2A?

Answer 12

• The risk of developing infections in cystic fibrosis can also be modified by a large number of gene variations
• Distinct from the Cystic fibrosis muation. One such gene is immunoglobulin Fc-gamma receptor II (FCGR2A) which if you have the variant can increase your change of developing a chronic Pseudomonas aeruginosa infection by 4 fold.

Question 13

What is Von Hippel-Lindau Syndrome? ow is it inherited?

Answer 13

-Von Hippel-Lindau syndrome (VHL) is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms, most frequently retinal, cerebellar, and spinal hemangioblastoma, renal cell carcinoma (RCC), pheochromocytoma, and pancreatic tumors.

Question 14

What does variation in CCND1 cause?

Answer 14

• Variation in cyclin D1 (CCND1) alters the phenotype of VHL
• 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 15

Are diseases just associated with a single gene?

Answer 15

• Some diseases are associated with only a single mutation for example sickle cell anemia
• Where as other disease can arise as the result of many mutations within the same gene.

Question 16

What are Duchhenne and Becker muscular dystrophy caused by?

Answer 16

-mutations in the dystrophin gene; the largest known human gene. the diseases are similar in the distribution of muscle wasting and weakness, which is mainly proximal

Question 17

What is difference between Duc and Beck muscular dystrophy?

Answer 17

1. Becker muscular dystrophy is a more mild phenotype with age of onset around 12 years; some patients have no symptoms until much later in life
2. Loss of ambulation also varies from adolescence onward, with death usually in the fourth or fifth decade
3. Mean age at DMD diagnosis was 4.6 years; wheelchair dependency had a median age of 10 years; cardiac muscle failure developed in 15% of patients with a median age of 21.5 years; with death at a median age of 17 years.

Question 18

What are the reasons for the difference between Duchenne and Becker muscular dystrophy?

Answer 18

• The reason for these differences in disease progression are the type of mutation in each.
  1. Both are the result of deletions in the dystrophin gene
  2. IDMD the mutation is a frame shift deletion and therefore no active dystrophin is produced.
  3. In Becker Muscular dystophy the mutation does not result in a frame shift and so active dystophin is produced al be it a shorter form this protein retains some of the activity of the longer form.
• This phenomenon is a common occurance with different gene phenotypes associated with different mutations.

Question 19

What are trinucelotide repeat disorders? What causes them?

Answer 19

• There are a large group of diseases termed trinucleotide repeat disorder
• The underlying cause of all these diseases is a trinucleotide repeat expansion
• This is a mutation in which a region of three repeated nucleotides in the genome increases in number during DNA replication

Question 20

What happens if there are fewer tan 27 repeats in the genome?

Answer 20

-If there are fewer than 27 repeats in the genome, these tend to be stable and the function of the protein remains normal

Question 21

What happens as the number of repeats increases?

Answer 21

1. reaches a thresehold above which they are no longer stable during DNA replication and the number of repeats increases during subsequent rounds of DNA replication

Question 22

What is the effect of the increase in trinucleotide repeats?

Answer 22

1. changes the protein function and a greater number of repeats results in a more severe phenotype
2. These types of disease are characterised by an earlier onset of disease and the greater severity of symptoms in each succeding generation, as the number of repeats increases.

Question 23

What is Huntington’s disease caused by?

Answer 23

-Huntington’s disease is caused by expansion of a region of cytosine-adenine-guanine (CAG)—repeats (i.e…. CAGCAGCAG…), in the huntington gene

Question 24

What does the CAG codon do?

Answer 24

• CAG is the codon for glutamine
• a series of these repeats results in the production of a chain of glutamine known as a polyglutamine tract or Poly Q tract (Q being the single letter code for gltumatine - PoM primer).

Question 25

What happens if there are fewer than 27 repeats in Huntington’s disease?

Answer 25

1. If there are fewer than 27 repeats, this is a normal phenotype and the region is stable.
2. If the number of repeats rises to 27–35, this results in an Intermediate phenotype with some minor effects, however the region of the DNA is not longer stable and the numbers of repeats can increase
3. As the repeats increase further to 36–39, this results in the characteristic phenotype but not all carriers will be affected by the disease.

Question 26

What happens once the number of repeats reaches 40 or more in Huntington’s disease?

Answer 26

-Once the number of repeats reaches 40 or more, this results in Huntington’s disease in all carriers.

Question 27

What causes phenoytype associated with disease to vary?

Answer 27

1. If individuals are genetically identical, the underlying cause of variation in the phenotype is likely to be environment
2. In non-identical individuals with the same mutation, e..g family members, variation could be the result of environmental interactions or the existence of variation in other genes which interact with the disease-causing mutation

Question 28

What happens in unrelated individuals?

Answer 28

-In unrelated individuals, different mutations or different disease-causing genes become an important source of phenotypic variation

Question 29

What could variation in phenotype also result from?

Answer 29

unstable mutations in trinucleotide repeat disease, resulting in an increased severity of disease