Presentation: Pregnancy at risk of cystic fibrosis

A couple attends their booking appointment and advises the midwife that the mother has a brother with cystic fibrosis (CF). She has been tested and is a known carrier. This was an unplanned pregnancy, so they have not been to the GP or to a clinical genetics team to have her partner tested for their CF carrier status.

• Carrier testing can be considered where there is a family history of CF.
• Where one parent is known to be a carrier of CF, the other parent can have carrier testing to determine the chance of a pregnancy having CF.
• Fetal testing should be discussed in cases in which both partners carry a confirmed pathogenic variant.

• Collect a detailed family and personal history from the couple.
• Follow local protocols regarding onward referral. This is likely to involve:
  • referral to local screening teams; or
  • referral to clinical genetics services if there is a family history of CF and/or known carrier status.
• 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.
• For information about the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Depending on the clinical scenario, a range of different genomic tests may be considered.
  • Carrier screening of the parent(s):
    • R185 Cystic fibrosis carrier testing. This can be offered by clinical genetics, fetal medicine, gynaecology, respiratory medicine and general practice specialties.
      • Note that this test includes the most common pathogenic variants in the Northern European population. It does not include all possible variants in the whole CFTR gene.
      • If a familial variant is known, you must notify the testing laboratory to ensure that this variant is analysed during testing.
      • If the test does not detect that the individual is a carrier of CF, a residual risk that they are a carrier will be reported. It is important to include the individual’s ethnicity on the test request form to ensure the accuracy of their residual carrier risk.
  • Prenatal testing in a pregnancy with a known familial disease-causing variant:
    • Non-invasive prenatal diagnosis (NIPD). This test has strict inclusion and exclusion criteria, which can be reviewed in the test directory. NIPD can be performed after eight to nine weeks of pregnancy (confirmed via ultrasound scan). Available tests include the following.
      • R304 NIPD for cystic fibrosis – haplotype testing. This test is available where both parents are carriers of a confirmed pathogenic variant. DNA must be available for both parents and either a previously affected fetus (or child) or a child/pregnancy that has been genetically confirmed as an unaffected non-carrier.
      • R305 NIPD for cystic fibrosis – variant testing. This test can be requested where the father carries a CFTR variant that is listed in the test directory eligibility criteria and the variant is different to the one carried by the mother. R305 testing excludes paternal inheritance only.
    • R448 Prenatal testing. Amniocentesis or chorionic villus sampling may be offered to test a pregnancy for CF where NIPD is not appropriate or available, or where it is a patient’s preference.
  • If a patient does not want CF testing during pregnancy, their infant can be tested after birth using the following.
    • R242 Predictive testing for known familial variant(s). This may be offered if the infant does not show any clinical signs of CF. It can only be requested by clinical genetics teams.
    • R184 Cystic fibrosis diagnostic test. This can be arranged if the infant/child shows clinical signs of CF as noted in the test directory eligibility criteria. The infant’s ethnicity needs to be noted on the test request form, as initial testing includes population-specific variants.
  • If the patient presents pre-conceptually, preimplantation genetic testing for monogenic conditions may be available. Referral via clinical genetics is required.
• None of the tests outlined above use whole genome sequencing, so you should use your local Genomic Laboratory Hub test order form and consent (record of discussion) form.
• For NIPD, including R304 and R305, a blood sample in a Streck tube is required. The testing laboratory can confirm their specific sample requirements.
• For invasive tests, an amniocentesis or chorionic villus sample or fetal blood sample (in an EDTA tube) is required, as well as a sample from the mother to test for maternal cell contamination. For many tests, parental samples are also needed or are helpful. For more information about different sample types, see Samples for genomic testing in rare disease.
• 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

• Genomics England: NHS Genomic Medicine Service (GMS) signed off panels resource
• NHS England: National Genomic Test Directory
• West Midlands Regional Genetics Laboratory: NIPD for cystic fibrosis (CF) – R304.1 (PDF, one page)

For patients

• Action Medical Research for Children: Cystic Fibrosis
• Cystic Fibrosis Trust
• NHS Health A to Z: Cystic fibrosis