Presentation: Patient with a family history of cystic fibrosis needing pre-conception advice

A couple presents for pre-conception advice. They are concerned as the man’s nephew has CF. They want to know what affects this may have on any future pregnancy.

• Those who would be eligible for CF carrier testing in England include:
  • prospective egg or sperm donors;
  • those who have a close relative with CF (up to the fourth degree – for example, a first cousin’s child or a closer relative), in which case you should test the partner whose family is affected;
  • the partner of a known CF carrier;
  • a couple that is closely consanguineous (first cousins) and from an ethnic group with a high carrier frequency; and
  • both parents of a fetus with echogenic bowel (where both parents are available for testing).
• Carrier testing can be requested from primary care and other clinical specialties depending on the clinical scenario and presentation.
• The process for requesting tests may vary locally and regionally; R185 Cystic fibrosis carrier testing is the National Genomic Test Directory’s clinical indication code for CF carrier testing.
• CF carrier testing identifies pathogenic variants responsible for about 90% of CF cases, though it does not exclude all rare variants. If the familial variant is known, this information should be supplied with the referral for genetic testing – the test can be modified to check for known rare variants.
• If one from the couple carries a variant, the status of the other partner is needed to determine risk to the pregnancy. This allows for consideration of the use of prenatal genetic selection to use an unaffected embryo.
• If the couple are already pregnant, prenatal diagnosis of the fetus can be offered.
  • Traditionally, prenatal diagnosis has required invasive testing via either chorionic villus sampling or amniocentesis. Increasingly, non-invasive prenatal diagnosis (NIPD) is used to analyse cell-free placental DNA fragments.

• Understand that CF follows an autosomal recessive inheritance pattern.
• If a couple presents for pre-conception advice with a relevant relative with CF:
  • Organise CF carrier testing, starting with the patient with the family history.
  • If that test identifies that a pathogenic variant is carried, then organise testing of the other partner to determine if there is risk to any future pregnancies.
• Explain that the 50 most common variants in White populations (plus the family variant, if available) are tested for as these are responsible for around 90% of cases. A ‘normal’ test result does not exclude the possibility they are a carrier, however. Document this in the patient record.
• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• Follow the local test requesting process.
  • You may be asked for the clinical indication code, which is R185 Cystic fibrosis carrier testing.
  • Blood samples should be taken in an EDTA tube (typically purple-topped) and sent in the usual sample collection service, where your usual provider lab will forward it to the genomics laboratory.
• If both in the couple are found to be CF carriers then refer them to the clinical genetics/genomics service with advice to return if they achieve pregnancy in the meantime.
• Carrier testing should be cascaded to first-degree relatives using ‘to whom it may concern’ letters.
  • These letters are generated for relatives to hand to their GPs.
• Where the couple is already pregnant, there should be urgent referral as per local pathways (usually clinical genetics or obstetric services). Include details of the affected family member, if the patient is able to give you these.
  • Referral is so that carrier testing and prenatal testing options can be discussed and offered in an appropriate timescale
  • Antenatal testing options include chorionic villus sampling, which can be offered from 10 weeks gestation, and NIPD, which can be offered from 9 weeks gestation.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• ​​NHS England: National Genomic Test Directory
• NHS South East Genomics: Genetic Test Ordering in Primary Care
• Patient.info: Cystic fibrosis
• Royal College of General Practitioners: RCGP Communicating Genomics: Autosomal Recessive Inheritance (video, two minutes)

References:

• Rohlfs EM, Zhou Z, Heim RA and others. ‘Cystic fibrosis carrier testing in an ethnically diverse US population’. Clinical Chemistry 2011: volume 57, issue 6, pages 841–848. DOI: 10.1373/clinchem.2010.159285

For patients

• Cystic Fibrosis Trust: Testing for cystic fibrosis carriers in families