Presentation: Pregnancy in which non-invasive prenatal diagnosis is planned

A couple attend their booking appointment and tell you that their first child was diagnosed with cystic fibrosis through newborn screening. They express concern about having a second child with the condition and wish to explore their options.

• When there is a family history of a condition in which the genetic cause (pathogenic variant) has been identified in the parents (either they are carriers for or they have been diagnosed with the condition).
• When parents have a child with a genetic condition but they themselves are not carriers.
• When parents wish to avoid invasive prenatal testing and the results of a genomic test are needed to inform pregnancy decisions, alleviate parental anxiety, and/or inform treatment during pregnancy or post birth.

• Collect a detailed family and personal history from the couple, noting any consanguinity and whether either parent has had genomic testing, as this can affect eligibility for non-invasive prenatal diagnostic (NIPD) testing.
• Refer the case to clinical genetics for review by a clinical geneticist or genetic counsellor.
• The clinical genetics team will review the NHS England National Genomic Test Directory eligibility criteria document to determine which tests are available for your patient. The test directory itself provides a list of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• NIPD testing can be either haplotype testing or mutation testing.
  • Haplotype testing requires samples from both parents and an affected child or pregnancy (DNA may already be in storage). It can report on both paternally and maternally inherited variants. The testing laboratory must be informed of the request in advance to ensure that the necessary samples and/or validation work can take place. Currently, testing is not available for consanguineous couples. Testing options can include:
    • R250 NIPD for congenital adrenal hyperplasia CYP21A2 haplotype testing (R251 non-invasive fetal sexing must first be performed to confirm the pregnancy is female);
    • R304 NIPD for cystic fibrosis haplotype testing;
    • R310 NIPD for Duchenne and Becker muscular dystrophy haplotype testing (R251 non-invasive fetal sexing must first be performed to confirm the pregnancy is male); and
    • R423 NIPD for retinoblastoma haplotype testing.
  • Variant (also known as mutation) testing requires either the father to be diagnosed with an autosomal dominant condition or, where both parents are carriers of an autosomal recessive condition, each to carry different variants. This testing only reports on paternally inherited variants, so invasive testing may be recommended to confirm whether a pregnancy will be affected by an autosomal recessive condition. The testing laboratory must be informed of the request in advance to ensure that the necessary samples and/or validation work can take place. Testing options can include:
    • R249 NIPD using paternal exclusion testing for very rare conditions where familial mutation is known – this can be for autosomal dominant and autosomal recessive conditions that are not covered by other test directory options.
    • R305 NIPD for cystic fibrosis mutation testing where only specific pathogenic variants can be detected.
    • R306 Alpert syndrome mutation testing.
    • R307 NIPD for Crouzon syndrome with acanthosis nigricans mutation testing.
    • R308 NIPD for FGFR2-related craniosynostosis syndromes mutation testing.
    • R309 NIPD for FGFR3-related skeletal dysplasia mutation testing.
    • R311 NIPD for spinal muscular atrophy mutation testing.
    • R423 NIPD for retinoblastoma. This is also available as haplotype testing, dependent on inheritance and family history. Your local GLH will advise you on the most appropriate test method.
  • NIPD may not be possible for multiple pregnancies. Please confirm with your local GLH prior to requesting testing.
  • Generally, NIPD is performed after eight to nine weeks of pregnancy, where the pregnancy has been confirmed via ultrasound scan. Please confirm test timing with your local GLH.
  • Please contact your local GLH in advance of the test request to confirm the test eligibility and to ensure the necessary samples and/or validation work can take place. The laboratory will advise if R389 NIPD pre-pregnancy test work-up is required.
• If the patient presents pre-conceptually, pre-implantation genomic testing for monogenic disorders may be available. Referral via clinical genetics is required.
• For NIPD, a blood sample in a Streck tube (or EDTA tube) is required. For many of the tests, partner samples are also needed or are helpful. Please refer to your local GLH for details of test request forms and where to send samples.
• A record of discussion form, or appropriate local consent form, is required for testing.
• 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 Birmingham Women’s and Children’s NHS Foundation Trust: Prenatal-reproductive genomic testing
• NHS England: National Genomic Test Directory
• NHS North Thames Genomic Laboratory Hub (Great Ormond Street Hospital for Children NHS Foundation Trust): Non-invasive prenatal diagnosis