Genetics

Question 1

Which of the following is not a feature of neurofibromatosis type 1?

A. Schwannomas
B. Autosomal dominant inheritence
C. Optic pathway gliomas
D. Lisch nodules
E. Tibial bowing

Answer 1

A - Schwannomas

Key differences between NF1 and NF2:
- cafe au lait macules seen in both but less common in NF2
- lisch nodules are never seen in NF2
- neurofibromas in NF1, schwannomas in NF2 (particularly vestibular schwanommas i.e. acoustic neuromas)
- cognitive impairment in NF1, not in NF2

Question 2

Which of the following genes is associated with HOCM?
A. MYBC3 gene
B. PKP2 gene
C. SCN5A gene
D. RYR2 gene
E. TTN gene

Answer 2

A. Cardiac mysosin binding 3 gene

PKP2 gene: arrythomogenic RV cardiomyopathy
SCN5A gene: LQTS (gain of function) and brugada (loss of function)
RYR2 gene: catecholaminergic polymorphic vt
TTN (titin) gene: dilated cardiomyopathy

Question 3

Raised CK, proximal weakness and and mild cognitive impairment.

Gene and syndrome?

Answer 3

Duchenne’s muscular dystrophy

Mutation of dystropin (DMD) gene. X-linked, typically frameshift mutation due to deletion of one or more exons

Question 4

Name the types of epigenetic mechanisms

Answer 4

• DNA methylation (hypo/hyper)
• histone modificatios (mehtylation, acetylation)
• chromatin modification
• X inactivation
• cellular differentiation

Question 5

What is lyonization?
What does it cause?

Answer 5

X inactivation

Results in variable disease courses in women who are heterozygous for certain mutations inc. X linked diseases

Question 6

In which of the following groups is the benefit of BRCA1/2 genetic testing most established?

A. Women 40 years of age
B. Men with breast cancer irrespective of age
C. Women 55yo with triple negative breast cancer
D. Women with epithelial ovarian cancer

Answer 6

A

B less well established
C <50yo + triple negative
D only for non-epithelioid ovarian cancer

Question 7

Tumors associated with VHL

Answer 7

hemangioblastomas of the cerebellum and spine
retinal angiomas
clear cell renal cell cancers
pheochromocytomas/paragangliomas
neuroendocrine tumors of the pancreas

Question 8

Define a missense mutation.
What does it result in?

Answer 8

Point mutation where a single base is change resulting in a single amino acid change

May lead to a loss of function, gain of function or altered function

Examples - sickle cell disease, proto-oncogenes

Question 9

Define a nonsense mutation.
What does it result in?

Answer 9

Point mutation where a single base change results in a premature stop codon.

Leads to haploinsuffiency

Question 10

List the following in their severity:
- frameshift mutation
- promotor mutation
- in frame mutation

Answer 10

Frameshift
In-frame
Promotor (variable pathogenecity)

Question 11

NOD2 loss of function is associated with which autoimmune disease?

Answer 11

Crohn’s disease

Question 12

ERAP1 deletion is protective for what

Answer 12

Ank spond

Question 13

What is imprinting caused by?

Answer 13

Methylation of cytosine residues on paternal/maternal alleles

Question 14

If 1 in 250,000 people have disease X, a non-lethal autosomal recessive disorder, what is the approximate carrier frequency of this disease?
a. 1/1000
b. 1/500
c. 1/250
d. 1/50
1/25

Answer 14

c) 1/250

People with disease X = qq = 1/250,000. √q² = √1/√25,000 = 1/500.
Carrier frequency = 2pq. Assume p = 1. 2 x 1/500 = 2/500 = 1/250.

Question 15

For a given autosomal recessive disease q = 0.01. Approximately what percentage of the population has two copies of the normal allele?
a. 2%
b. 19%
c. 90%
95%
d. 98%

Answer 15

Answer: E

q = 0.01. p + q = 1. p = 1 – 0.01 = 0.99.
Two copies of the normal allele = PP. PP = 0.99 x 0.99 = 0.9801 = 98%.

Question 16

The risk of a healthy 70-year-old person developing dementia over the next five years is 5%.
10% of the total population carry one or two ApoE4 alleles and have a threefold increased risk of developing dementia during this interval.

What is the best estimate of the proportion of people developing dementia during this interval who do not have one or two ApoE4 alleles?

A. 70%
B. 90%
C. 30%
D. 10%

Answer 16

90% (population with no alleles) x 5% (normal population risk) = 450

10% (population with allele) x 15% (allele population risk) = 150

Total population = 600

450 (Population without allele)/600 (total population) = 70%

Answer = A

Question 17

What does chromosomal microarray pickup?
What does it not?

Answer 17

Chromosomal deletions and duplications

Does not pick up single nucleotide changes eg. missense variant/nonsense variant/frameshift
variant etc.

Cannot detect triplet repeat expansion disorders