DNA Analysis

Question 1

What is the definition of penetrance?

Answer 1

Likelihood of a having a disease if you have a mutation

Question 2

What are Mendelian disorders?

Answer 2

Diseases that segregate in families according to the manner predicted by Mendel’s law

Question 3

What is used to help build up the sequence of an individual in NGS?

Answer 3

Reference sequences = bases off of most common sequence in Caucasian males

Question 4

What is a variant?

Answer 4

Any change in DNA sequence = may be pathogenic or benign

Question 5

What is the term mutation commonly used to describe?

Answer 5

Commonly used to describe a pathogenic variant

Question 6

What is a polymorphism?

Answer 6

Variant that is prevalent in the population = often used to imply benign

Question 7

What are the potential explanations for a genetic change?

Answer 7

Polymorphism, a disease-causing mutation or a variant of unknown significance

Question 8

How many causative genes are present in a Mendelian disorder?

Answer 8

Only one causative gene

Question 9

What are some indications a variant is pathogenic?

Answer 9

Causes frame shift or premature stop
In highly conserved area
Changes amino acid sequence 
Causes intron to remain
Found in low percentage of people

Question 10

What questions must be considered when trying to identify a causative variant?

Answer 10

Is it in a coding bit of the gene?
Does it affect the gene?
Is it in a disease-causing gene?
Is it a known polymorphism?
Does the pattern of inheritance match?

Question 11

What are the different classes of variants?

Answer 11

Class 1 = definitely benign
Class 2 = probably benign (90+%)
Class 3 = variant of uncertain significance
Class 4 = probably pathogenic (90+%)
Class 5 = definitely pathogenic

Question 12

How much of the genome is exons that code for something?

Answer 12

Only 1-2%

Question 13

What effect may an exonic variant have?

Answer 13

Change amino acid sequence
Create stop
Cause frameshift
Have no effect

Question 14

Are intronic variants likely to have any effect?

Answer 14

No, have low likelihood of effect

Question 15

What are the differentials of sudden death in a patient?

Answer 15

Intracranial event = subarachnoid haemorrhage, massive stroke
CV event = MI, cardiac arrhythmia, dissecting aortic aneurysm

Question 16

What are the types of dissecting aortic aneurysm?

Answer 16

Sporadic of genetic (autosomal dominant) = look for family history and additional characteristics

Question 17

What are some genes implicated in genetic dissecting aortic aneurysms?

Answer 17

ACTA2 = 10%
TGFBR2 = 4%
TGFBR1 = 1%

Question 18

What are some features of Marfan’s syndrome?

Answer 18

Dilated aorta, long fingers and lens dislocation
Mutation in fibrillin = 1 in 5000 people
Autosomal dominant

Question 19

What are some features of Loeys Dietz syndrome?

Answer 19

Bifid uvula
Aortic aneuryms
Tortuous blood vessels

Question 20

Where are the causative mutations of long QT syndrome located?

Answer 20

Usually in ion channels for the heart = occur in 1 in 2000 people

Question 21

Why is NGS best for diagnosing long QT syndrome?

Answer 21

Ion channel genes are long

Question 22

What gene is implicated in familial hypercholesterolaemia?

Answer 22

PCSK9 gene = mutation present in 1 in 500 people

Question 23

How is population risk assessed for multifactorial conditions?

Answer 23

Phenotype testing