Cystic Fibrosis Newborn Screening

Question 1

Cystic fibrosis is the most common, severe autosomal recessive disease in Europeans. What is the incidence?

Answer 1

Approx 1 in 2500

Question 2

What is affected in classical CF?

Answer 2

Lungs, pancreas, intestines, biliary tract, sweat glands and reproductive tract

Question 3

What is the typical presentation in classical CF?

Answer 3

• Infant with recurrent chest infections
• Failure to thrive
• Malabsorption

Question 4

What is the major cause of morbidity and mortality in classical CF?

Answer 4

• Chronic lung infection leading to fibrosis and bronchiecstasis which lead to respiratory insufficiency
• untreated will result in death by 5 yrs but with treatment it is approx 33 yrs

Question 5

CFTR-related disease gives a milder spectrum of symptoms compared to classic CF. What are some of the symptoms?

Answer 5

• CBAVD, azoospermia, oligospermia
• Idiopathic pancreatitis
• Disseminated bronchiecstasis
• Allergic bronchopulmonary aspergillosis
• Chronic rhinosinusitis

Question 6

A randomised controlled trial as part of the Wisconsin CF neonatal screening project demonstrated what clear benefits of the programme?

Answer 6

• Long term nutrition
• Cognitive function
• Early treatment in specialist centres
• Cascade screening/reproductive decision making
• Health economics

Question 7

When and how is the blood taken for the newborn screening programme in England?

Answer 7

Heel prick/blood spot at Day 5

Question 8

What biomarker is elevated in the blood of babies with CF?

Answer 8

Immunoreactive trypsinogen (IRT)

Question 9

What are the limitations associated with IRT in newborn CF screening?

Answer 9

• IRT is a poor marker for during the first few days of life (3-10% PPV)
• Better at 2-4 weeks (approx 50% PPV)

Question 10

What should be maximised in the context of CF newborn screening?

Answer 10

Diagnosis of CFTR defects producing preventable or treatable disease (respiratory, digestive) in infancy or childhood

Question 11

What should be minimised in the context of CF newborn screening?

Answer 11

• Second samples
• Diagnostic delay
• Detection of unaffected heterozygotes
• Diagnosis of very mild forms of CFTR defect producing late-onset, essentially unpreventable, disease

Question 12

What is the chosen strategy for CF newborn screening in England?

Answer 12

• Combination of biochemical and genetic testing
• Measurement of IRT at day 5 (and day 28)
• 2 stage testing of CFTR gene

Question 13

What are the issues surrounding IRT levels and meconium ileus in the context of CF newborn screening?

Answer 13

• CF infants with meconium ileus may show a normal IRT
• These, and babies at high risk due to family history or who have shown echogenic bowel, should be investigated according to clinical circumstances as well as being screened

Question 14

The first stage of DNA analysis in CF newborn screening involves what?

Answer 14

• 4 most common severe mutations that account for approx 85% of UK mutation alleles
• DeltaF508, 621+1G>T, G542X, G551D
• Genotyping done by ARMS PCR or pyrosequencing

Question 15

The second stage of DNA analysis in CF newborn screening involves what?

Answer 15

• Extended mutation panel
• CFEU2 kit (ARMS PCR, 50 mutations)
• CF OLA kit (multiplex PCR and oligonucleotide ligation assay, 32 mutations)

Question 16

Give an example of a mild mutation in the context of CF newborn screening

Answer 16

• R117H (p.Arg117His)
• deltaF508/R117H(7T) can be associated with mild lung disease, CBAVD or no symptoms (especially in females)
• a follow up of 9 of these individuals identified via newborn screening found no clinical symptoms in any at mean age of 7