27 - Genetic Pathology in Patient Management

Question 1

Technical challenges in genetic pathology

Answer 1

• DNA quality and quantity
• Availability of positive and negative DNA controls (difficult in rare disease)
• “Tricky” genomic regions (e.g. repetitive sequence, pseudogenes, GC rich regions)

Question 2

Interpretive challenges in genetic pathology

Answer 2

• Limitations in ability to demonstrate the effect of DNA level changes on protein and cellular function in clinical laboratories
• Limitations in knowledge of genetic causes/mechanisms (e.g. yet to be discovered genes, incomplete penetrance)

Question 3

Possible findings from a targeted test

Answer 3

The pathogenic variant(s) you are looking for is either there or not there

Question 4

Possible findings from an untargeted test (whole gene or multiple genes)

Answer 4

• More than one variant found, which is pathogenic?
• May detect variants of uncertain clinical significance
• Nay detect incidental/secondary findings

Question 5

Why do genetic testing

Answer 5

• Diagnosis and treatment (pre and post natal)
• Identification of at-risk, asymptomatic family members
• Disease prognosis
• Disease monitoring
• Drug sensitivity and resistance

Question 6

What is clinical utility

Answer 6

• Does knowing that genetic variant is present change anything for patient?
• How can we use genetic testing to improve patient care
• What are the benefits and challenges of genetic testing for patients and clinicians?

Question 7

Nonsense-mediated mRNA decay

Answer 7

• A surveillance pathway that exists in all eukaryotes
• Main function to reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop
  codons
• Consequence is no protein product is produced (null variant, loss of function)

Question 8

Example of therapy based on genotype

Answer 8

Ivacaftor

Question 9

Ivacaftor

Answer 9

Potentiates the CFTR channel (increased probability of ‘open’ conformation)

Question 10

Alpha1-antitrypsin deficiency (AATD)

Answer 10

• Autosomal recessive condition
• Caused by pathogenic variants in the SERPINA1 gene (encodes alpha1-antitrypsin)
• Alpha1-antitrypsin (AAT) is a protease inhibitor (prevents enzymes from degrading protein)

Question 11

Ethical challenges in genetic pathology

Answer 11

• Decisions made based on genetic testing
• Implications for extended family

Question 12

Decisions made based on genetic testing

Answer 12

• Life choices (e.g. marriage, family planning)
• Continuation of pregnancy
• Insurance implications

Question 13

Implications for extended family

Answer 13

• Are they at risk of disease? Do they want to know? Should they know?
• Guilt/feelings associated with passing on disease, or not being affected when other family members are
• Testing of one family member may reveal the genetic status of another who does not wish to know