Phenotypic variability

Question 1

How do gene/environmental interactions contribute towards phenotypic variance?

Answer 1

Contribute to the progression and outcome of the disease for each patient.
Affects prognosis

Question 2

What is multiple endocrine neoplasia type 1 (MEN1)?

Answer 2

Increased chance of developing adenomas within endocrine tissue.

Question 3

Which genes are mutated within MEN1?

Answer 3

Mutation within tumor suppressor gene (synthesizes menin).

Question 4

What is the inheritance pattern for MEN1?

Answer 4

Autosomal dominant inherited conditions

Question 5

How do environmental triggers affect the phenotypic expression of MEN1?

Answer 5

Promotes tumour formations, tumours associated with parathyroid gland, pancreatic islet & anterior pituitary.

Question 6

Which protein is mutated within hereditary hemochromatosis?

Answer 6

HFE

Question 7

Which receptor is bound to transferrin, enabling iron entry into hepatocytes?

Answer 7

Transferrin receptor I

Question 8

Which hormone regulates iron release within enterocytes?

Answer 8

Hepcidin

Question 9

What is the pathophysiology of hereditary hemochromatosis?

Answer 9

HFE protein regulates iron levels within hepatocytes by preventing transferrin from binding to transferrin receptor I. HFE mutation reduces iron transportation into the live, therefore hepcidin synthesis is reduced. This causes increase ferroportin release of iron from enterocytes, resulting in iron overload.

Question 10

What percentage of patients with hereditary hemochromatosis have clinically relevant iron accumulation?

Answer 10

10%

Question 11

Why are women more likely to be protected from hereditary hemochromatosis?

Answer 11

Menstrual bleeding

Question 12

What are genetic modifiers?

Answer 12

Life-course of disease and symptoms present are modified by presence of other genes. These gens can either improve or worsen the condition.

Question 13

Name three cystic fibrosis genetic modifiers

Answer 13

delf5f08, TFB1 gene, FCGR2A

Question 14

How does the delf5f08 gene alter the phenotypic expression of CF?

Answer 14

Homozygotes of the gene mutation classified with severe/mild lung disease

Question 15

How does the TGFB-1 gene alter the phenotype of CF?

Answer 15

Encodes for transforming growth factor beta-1, variants associated with severe lung disease phenotype. Increases lung inflammation.

Question 16

Which gene increases the risk of developing respiratory tract infections with patients of CF?

Answer 16

Immunoglobulin Fc-gamma receptor II (FCGR2A)

Variant increases chance of developing chronic pseudomonas aeruginosa infection by 4 fold

Question 17

Which is VHL?

Answer 17

Von-Hippel Lindau syndrome
Dominant inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms. Retinal, cerebellar and spinal hemangioblastoma, renal cell carcinoma, pheochromocytoma, and pancreatic tumors

Question 18

Which gene modifier alters the phenotype of VHL?

Answer 18

Cyclin D1 (CCND1)
G allele increases number of retinal angiomas compared with AA homozygotes. G allele associated with earlier diagnosis of CNS hemangioblastoma by 2 fold.

Question 19

What is the function performed by the cyclin d1 receptor?

Answer 19

Cyclin d1 regulator of cell cycle progression, overexpression leads to the development of cancer

Question 20

Which protein is involved in muscular dystrophy?

Answer 20

Dystrophin

Question 21

Which are the two main muscular dystrophy conditions?

Answer 21

Becker muscular dystrophy

Duchenne muscular dystrophy

Question 22

When is the age of onset of Becker muscular dystrophy?

Answer 22

12 years old, loss of ambulation varies from adolescence onwards

Question 23

When does death usually occur with patients expressing BMD?

Answer 23

Death in the fourth/fifth decade

Question 24

When is the age of onset for DMD?

Answer 24

4.6 years

Question 25

When do patients with DMD become wheelchair dependent?

Answer 25

10 years

Question 26

What percentage of patients with DMD develop cardiac failure?

Answer 26

15% of patients, with a median age of 21.5 years

Question 27

When is the median death for patients with DMD?

Answer 27

17 years

Question 28

Which type of gene mutation is associated with muscular dystrophy disorders?

Answer 28

Deletions

Question 29

How does a gene mutation cause DMD?

Answer 29

A deletion within the dystrophin gene causes a frameshift deletion, thus this means no active dystrophin is produced (triplet of a sequence of bases altered, altering codon sequence)
Presence of premature stop codon

Question 30

How does BMD mutation occur?

Answer 30

Deletion causes stop codon, therefore a truncated functional dystrophin protein is produced

Question 31

What are unstable gene mutations?

Answer 31

Diseases termed trinucleotide repeat disorders, the underlying cause of the disease is trinucleotide repeat expansion. Mutation whereby a region of three repeated nucleotides within the genome increases in frequency during DNA replication.

Question 32

Below which number of repeats conforms for gene stability and protein functionality?

Answer 32

27 repeats

Question 33

What is DNA slippage?

Answer 33

Increased repeat frequency exceeds the stability threshold, whereby mutation loses stability during DNA replication and the number of repeats increases during subsequent rounds of DNA replication – Increase trinucleotide repeats, changing protein function

Question 34

What is the relationship between repeat frequency and phenotypic severity?

Answer 34

Greater number of repeats results in increased severity of phenotype. Characterized by an earlier onset of disease, greater severity of symptoms in each succeeding generation as the number of repeats increases.

Question 35

Which trinucleotide sequence is associated with Huntington’s disease?

Answer 35

CAG

Question 36

What causes Huntington’s disease?

Answer 36

Caused by the expansion of the region of the huntingtin gene (Cytosin, adenine, guanine), monogenetic (affecting only one gene), a neurodegenerative disorder

Question 37

What is the inheritance pattern for Huntington’s disease?

Answer 37

Autosomal dominance

Question 38

Which amino acid is encoded by CAG?

Answer 38

Glutamate

Question 39

What is formed from multiple glutamate polypeptide sequences?

Answer 39

Poly Q tract (Polyglutamine)

Question 40

Fewer than ___ CAG repeats is considered stable?

Answer 40

27

Question 41

Between which CAG repeat range forms an intermediate phenotype?

Answer 41

27-35 repeats

Question 42

What number of CAG repeats forms the characteristic phenotype?

Answer 42

36-39 (Not all carries affected by disease)

Question 43

What number of CAG repeats affects all carriers?

Answer 43

40+