Presentation: Pregnancy at risk of an autosomal recessive condition

A woman is eight weeks pregnant with her first child. She and her male partner are both carriers of an autosomal recessive genetic condition. The couple present at their booking appointment with questions about the risk to the pregnancy and whether there is any genomic testing available.

Genomic testing should be considered if:

• an autosomal recessive condition is suspected or diagnosed in either the maternal or paternal family;
• either parent is a known carrier for an autosomal recessive condition; or
• clinical features in the fetus (found during a fetal echocardiogram or an anomaly scan, for example) are suggestive of an autosomal recessive condition.

• Collect a detailed family and personal history from the couple, including details of previous genomic testing in the family (if known).
• Refer one or both parents to a clinical genetics department for review by a clinical geneticist or genetic counsellor. If either the pregnant woman or her partner has already received genomic testing and counselling for a known recessive condition in the family and was found not to be a carrier, a referral is not routinely required. If this is uncertain, referral is advised.
• The clinical genetics team will review the National Genomic Test Directory eligibility criteria to determine which tests are available. The directory itself provides a list of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• Testing options may include the following.
  • Where there is a known maternal and paternal disease-causing variant:
    • R448 Prenatal testing (this is targeted variant testing): amniocentesis or chorionic villus sampling may be offered to test a pregnancy for an autosomal recessive condition in cases in which non-invasive prenatal diagnosis (NIPD) is not appropriate or available, or where it is the individual’s preference;
    • R249 NIPD using paternal exclusion testing for very rare conditions where familial variant is known:
      • may be an option if the mother and father carry different disease-causing variants in the same gene;
      • may only report the presence of the paternal variant, depending on the type of NIPD (please contact your local Genomic Laboratory Hub (GLH) in advance of testing to confirm).
    • Note that certain conditions (such as cystic fibrosis, spinal muscular atrophy and congenital adrenal hyperplasia) have specific test directory indications and associated codes. For more information, please see Pregnancy at risk of cystic fibrosis.
  • Where there is a known maternal and paternal disease- causing variant, preimplantation genetic testing for monogenic disease may be available in a future pregnancy. Referral via clinical genetics is required.
  • Where there is a suspected maternal and paternal disease-causing variant:
    • try to confirm the disease-causing variant in each family;
    • test each partner for their family’s disease-causing variant;
    • if unable to confirm the family’s disease-causing variant, consider the appropriate genomic test according to the features of the affected individual (this may be a gene panel test or a test for common variants); and
    • offer testing to other family members if the index patient has a disease-causing variant.
  • If there are clinical features in the fetus suggestive of an autosomal recessive condition, the test is R21 Fetal anomalies with a likely genetic cause: fetal exome sequencing. Referral to clinical genetics is required.
• None of the tests outlined above use whole genome sequencing, so you should use your local GLH test order form and consent (record of discussion, or RoD) form.
• Parental samples may be needed for interpretation of the proband’s result. Parental samples can be taken alongside that of the proband, and their DNA stored, or can be requested at a later date if needed.
• For R21 Fetal anomalies with a likely genetic cause, you will need to:
  • ensure that the required multidisciplinary discussions have taken place, including fetal medicine, clinical genetics and the regional specialist R21 laboratory, and that there is an agreement that R21 can be offered;
  • inform your local laboratory of the plan for R21 testing, so that they can arrange the necessary exports to the specialist R21 laboratories in a timely fashion;
  • fill in the R21-specific test order form;
  • take informed consent for both parents, documented on R21-specific RoD forms;
  • send blood samples for both parents to the local laboratory (if only one parent is available, let the lab know – testing can still proceed, but there will be a small reduction in diagnostic yield); and
  • arrange and send a chorionic villus sample or amniocentesis sample for the fetus.
  • Note that, in Scotland, referral to clinical genetics is required for consideration of rapid prenatal exome testing.
• For NIPD, a blood sample in a Streck tube is required. 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 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

• NHS England: National Genomic Test Directory
• NHS North Thames and NHS West Midlands, Oxford and Wessex Genomic Laboratory Hubs: National Genomic Test Directory Clinical Indication R21 Rapid prenatal exome sequencing test request (PDF, two pages)
• NHS North Thames and NHS West Midlands, Oxford and Wessex Genomic Laboratory Hubs: Record of discussion regarding prenatal exome sequencing (PDF, two pages)

For patients

• NHS North Thames and NHS West Midlands, Oxford and Wessex Genomic Laboratory Hubs: Information on prenatal exome sequencing for parents (PDF, two pages)