Cystic fibrosis

Question 1

What is the incidence of cystic fibrosis? (2)

Answer 1

• 1 in 2500 live births
• Carrier frequency 1 in 25

Question 2

What is the life expectancy of cystic fibrosis?

Answer 2

Approximately 42 years

Question 3

What does the CFTR gene code for? (5)

Answer 3

• Cystic fibrosis transmembrane conductance regulator (chloride channel)
• In secretory epithelial cells which produce mucus, sweat, saliva, tears, digestive enzymes
• Lubrication of airways, digestive system, reproductive system
• Mutations cause defective chloride transport resulting in abnormally thick mucus

Question 4

Which systems are affected by cystic fibrosis? (4)

Answer 4

• Pulmonary
• Pancreatic
• Gastrointestinal
• Reproductive (males)

Question 5

What are the pulmonary features of CF? (3)

Answer 5

• Thick mucus blocks airways (COPD)
• Leads to bronchiectasis (persistent and progressive dilation of bronchi or bronchioles)
• Increased susceptibility to chronic respiratory infections

Question 6

What are the reproductive features of CF? (5)

Answer 6

• 95% of males with CF are infertile
• Obstructive azoospermia
• Congenital absence of the vas deferens
• Can be seen as an isolated feature
• Females are fertile but some evidence of abnormal cervical mucus causing infertility

Question 7

How is CF diagnosed? (2)

Answer 7

• Sweat chloride test (pilocarpine stimulated)
• Genetic testing

Question 8

Why would a patient be referred for CF testing? (4)

Answer 8

• Diagnostic
• Family history
• Infertility
• Newborn screening

Question 9

What features suggest diagnostic testing for CF? (5)

Answer 9

• Recurrent chest infection
• Failure to thrive
• Chronic pancreatitis
• Fetal echogenic bowel
• Meconium ileus (bowel obstruction)

Question 10

What is newborn screening for CF? (2)

Answer 10

• Guthrie heel prick test
• Raised IRT indicates the need for further investigation

Question 11

Where is the CFTR gene located?

Answer 11

7q31

Question 12

How is CF inherited?

Answer 12

Autosomal recessive

Question 13

What are the features of CFTR mutations? (3)

Answer 13

• Over 2000 mutations throughout 24 exons
• Most variants are missenses and small deletions
• Variant frequencies vary between populations

Question 14

What is the most common CFTR mutation? (2)

Answer 14

• DeltaF508 (p.Phe508del)
• 3 nucleotide deletion causing loss of phenylalanine amino acid in exon 10

Question 15

What are the classes of CFTR mutation? (5)

Answer 15

• Class I = protein production
• Class II = protein processing
• Class III = gating
• Class IV = conduction
• Class V = insufficient protein

Question 16

Which classes of CFTR mutation results in no functional protein? (2)

Answer 16

• Classes I-III
• Classic CF

Question 17

Which classes of CFTR mutation results in some functional protein? (2)

Answer 17

• Classes IV-V
• Mild CF

Question 18

Why is there such a high frequency of CFTR heterozygotes? (2)

Answer 18

• Overstimulation of CFTR in intestinal epithelial cells by bacterial toxins (e.g. cholera) causes secretory diarrhoea
• CFTR mutations resulting in less CFTR protein provides a selective advantage

Question 19

What is the genetic testing for CF? (4)

Answer 19

• Elucigene CF-EU2v1 assay
• PCR based assay
• Tests for the 50 most common variants
• Useful to know a persons’ ethnicity as variant frequency varies in populations

Question 20

How does the CF-EU2V1 arms assay work? (5)

Answer 20

• Primer sequence is specific for the variant
• If not present, primer doesn’t bind = no PCR product
• If present, primer binds = PCR product
• Also contains a primer for WT so if heterozygous there will be a WT and a variant PCR product
• Blue peak indicates a pathogenic variant

Question 21

What does compound heterozygous mean?

Answer 21

Patient has 2 different pathogenic variants causing recessive disease

Question 22

Why is parental testing recommended following CFTR diagnosis?

Answer 22

• To confirm whether the 2 mutations are on the same or different alleles
• Expected to be on different alleles

Question 23

What is the treatment for the respiratory symptoms of CF? (8)

Answer 23

• Physiotherapy
• Oral/inhaled/IV antibiotics
• Bronchodilators
• Mucolytic agents to reduce mucus viscosity
• Anti-inflammatory agents
• Home oxygen therapy
• Lung/heart-lung transplant
• Lifestyle (exercise)

Question 24

What is the treatment for the GI symptoms of CF? (4)

Answer 24

• High calorie, high fat diet
• Supplemental feeding
• Oral pancreatic enzyme replacement therapy
• Tube feeding

Question 25

What is the treatment for the reproductive symptoms of CF? (2)

Answer 25

• CBAVD = congenital bilateral absence of the vas deferens
• ART = assistive reproductive techniques such as microscopic epididymal sperm aspiration (MESA) and intracytoplasmic sperm injection (ICSI)

Question 26

What molecular therapies are available for CF? (3)

Answer 26

• Symkevi = combination of ivacaftor and tezacaftor, effective for homozygous F508del and compound heterozygous for F508del and another
• Kalydeco = ivacaftor only, for gating mutations
• Orkambi = combination of ivacaftor and lumacaftor, effective for homozygous F508del, slows lung function decline by 42%

Question 27

What proportion of CF patients in the UK are homozygous for F508del?

Answer 27

50%

Question 28

How does ivacaftor work?

Answer 28

Increases open probability (gating mutations) to improve chloride transport

Question 29

How does lumacaftor work?

Answer 29

Improves CFTR trafficking to the membrane