Cystic Fibrosis (CF)

Cystic Fibrosis (CF) is the most common life-threatening autosomal recessive condition in Caucasians. It is due to mutations within the CF Transmembrane Conductance Regulator (CFTR) gene on chromosome 7.

Mutations affect sodium and chloride transport across cell membranes and as a result cause production of thickened secretions within airways and ducts.

In the UK, the incidence is 1 in 2500. The condition is less common in those of Asian and African ancestry.

Testing for Cystic Fibrosis (CF): Information for GPs

Presentation and Outcomes

There are several ways in which CF can present, and of course since November 2007, newborn screening for CF has been introduced to identify babies with CF, prior to them presenting clinically. 

There are different forms of CF and diagnostic criteria have been defined by Rosenstein & Cutting (1998).

Classical CF consists of obstructive lung disease, bronchiectasis, exocrine pancreatic insufficiency or infertility in males due to congenital bilateral absence of the vas deferens (CBAVD). It can present with recurrent respiratory infections and failure to thrive, as well as in older children, nasal polyps and rectal prolapse. In the newborn, presentation can be with meconium ileus and intestinal obstruction.

CF can also present with male infertility due to CBAVD, but without any of the other problems. Because the mutations affect transport of sodium and chloride across cell membranes, a common finding is an increase in the sodium concentration within sweat. This is the basis of the sweat test which is the gold standard test for classical CF.

Genetics

There are over 1000 mutations identified within the CFTR gene. The commonest mutation is the ΔF508 mutation (70%). In the UK, the CF carrier rate, for one CF mutation, is 1 in 20 to 1 in 25, with a recurrence risk of 1 in 4 in each pregnancy for parents who are both carriers.

Some mutations are more common within certain ethnic groups.  Some mutations cause fewer problems, so depending on the combination of mutations inherited, the form of CF, age of onset, severity and progression of CF can vary. For example, pancreatic insufficiency with variable lung disease is a common presentation in those who inherit two copies of ΔF508.

Carrier testing and screening in adulthood

As with any genetic condition being tested for, the family members should receive pre-test counselling to enable informed consent. Siblings of a child with CF, or a CF carrier, will not be screened until old enough to understand the implications of the test.

If a diagnosis of CF is made, the family may be referred for genetic counselling by the GP or the CF team, if the family wants this. Issues to discuss would include cascade screening of family members for CF mutations.

If both parents are carriers there is a 1 in 4 chance in every pregnancy of having a child with CF. Pre-implantation Genetic Diagnosis (PGD) can be offered for CF.

Parents may not wish to consider PGD, but in subsequent pregnancies parents can be offered prenatal diagnosis via chorionic villous sampling (CVS) at 11 weeks gestation.

The newborn screening programme will identify some babies as carriers. For parents of these babies there is still a 1 in 200 chance that a subsequent pregnancy could be affected by CF.

The parents may wish to see a genetic counsellor to look at the issue of carrier testing.

Testing for Cystic Fibrosis (CF): Information for GPs

Key facts

• CF is a genetic condition that affects the lungs and pancreas, liver and intestines. The majority of people are diagnosed in infancy, but some non-classic (often milder) forms can present later in childhood or in adulthood. It often affects male fertility.
• CF is caused by mutations in the CFTR gene. Non-classic forms may be termed ‘CFTR-related disorders’.
• CF is inherited in an autosomal recessive pattern. Affected people will usually have two CFTR mutations. Carriers will usually have just one CFTR mutation. The Northern European population carrier frequency is ~ 1 in 22.
• Being a CF carrier has no known health implications.
• Current testing covers a panel of 50 mutations most commonly seen in the Northern European population. A normal result does not completely rule out the chance of someone being a carrier, and a residual risk is usually given by the laboratory. People from different ethnic populations also may carry other mutations that are not detected on this test.
• Couples who are both carriers have a 1 in 4 chance of having an affected child. Reproductive options are available and can be discussed with the patients when referred to Clinical Genetics. 

Who to test in Primary Care

• Couples who are both carriers of CF
• Couples with an affected child/pregnancy.
• Pregnant women with a family history/partner family history of CF (please refer both the pregnant woman and their partner if possible). These will be handled as an urgent referral, please send these to us promptly and highlight it is urgent.  These can also be emailed to nuth.fetalgenetics@nhs.net

Please refer the following people to Clinical Genetics for testing (see enclosed letter for detail)

• Couples who are both carriers of CF, and couples with an affected child.
• Pregnant women with a family history/partner family history of CF (please mark as urgent)
• Couples in a consanguineous relationship (1st cousins or closer)

How to test:

• Samples can be sent to your local hospital pathology department as routine, who will then forward them to the genetics laboratory. 

How to test

• 2 to 5ml blood in EDTA (anticoagulant) tube sent with DNA request card to Northern Molecular Genetic Service via your local hospital pathology department.
• Include name of affected or carrier relative on sample referral
• Sample referral forms can be downloaded at Clinical Services – Newcastle Laboratories or requested (free of charge) from Hazel Forrest, Secretary to Molecular Diagnostic team (0191 241 8754).
• Results take approximately 4 weeks.  Urgent testing for pregnant couples is available by referral to Clinical Genetics.

Interpretation of results

The laboratory report will contain information to help guide the risk assessment and any further management. Please also refer to the following table.

Information/support for patients:

If you require further guidance please contact the Clinical Genetics team and ask to speak with the duty genetic counsellor, or email nuth.dna@nhs.net