Presentation: Fetus with an isolated congenital anomaly

A woman presents at 20 weeks’ gestation for a routine anatomy scan in a low-risk pregnancy. The sonographer detects an apparently isolated congenital anomaly. The remainder of the anatomy scan appears normal. First-trimester screening was low risk and there were no other concerning features.

• Discussion regarding genomic testing is dependent on the anomaly detected.
• Testing should be considered where there is a family history of a genetic condition that is associated with the isolated anomaly seen on the ultrasound.
• Details about genomic testing for specific congenital anomalies can be found in other GeNotes articles. See, for example:
  • fetus with a brain anomaly;
  • coarctation of the aorta;
  • ventriculomegaly;
  • fetus with a diaphragmatic hernia;
  • fetus with ambiguous genitalia;
  • fetus with raised nuchal translucency;
  • fetus with cystic renal disease; and
  • fetus with an isolated short femur.
• The National Genomic Test Directory clinical indication R21 Fetal anomalies with a likely genetic cause is typically considered when more than one congenital anomaly is found; however, some isolated anomalies are eligible. These include:
  • major central nervous system anomalies (not including neural tube defects);
  • anomalies of the corpus callosum (partial or complete agenesis);
  • large echogenic kidneys with a normal bladder;
  • isolated non-immune fetal hydrops (detected after 18 weeks’ gestation with normal array CGH); and
  • small for gestational age (abdominal circumference and head circumference <3rd centile, with no evidence of placental insufficiency, no family history of fetuses found to be small for gestational age and no maternal history of systemic lupus erythematosus).

• 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.
• Refer to local guidance regarding fetal medicine referral. Further review in a fetal medicine unit is usually warranted.
• A fetal medicine review will determine whether genomic testing is appropriate, and a referral to clinical genetics will be considered (note, however, that referral to clinical genetics is not routinely indicated for a fetal isolated congenital anomaly.
• The fetal medicine team will decide which genomic testing is most suitable for this case and/or will discuss the case with a multidisciplinary team, depending on the specific clinical scenario and the family’s wishes.
  • Where there is an isolated anomaly:
    • R22 Fetus with a likely chromosomal abnormality. This will process both:
      • R22.1 Genome-wide common aneuploidy testing; and
      • R22.2 Chromosomal microarray.
  • For certain significant or complex anomalies and/or where the above testing is non-diagnostic, fetal exome sequencing may be considered:
    • R21 Fetal anomalies with a likely genetic cause: Fetal exome sequencing.
      • Referral to clinical genetics and/or multidisciplinary discussion is required.
      • The clinician requesting the test will be required to complete a record of discussion (RoD) form.
  • Where a specific genetic condition is considered likely, or there is a relevant family history, further guided genomic testing my be recommended.
• None of the tests outlined above use whole genome sequencing, so you should use your local Genomic Laboratory Hub test order form and consent (RoD) form.
• Parental samples may be needed for interpretation of the child’s result. Parental samples can be taken alongside that of the child, 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.
• All of the above tests are DNA based and require an amniocentesis or chorionic villus sample, or a fetal blood sample in an EDTA (typically purple-topped) tube. 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

• National Congenital Anomaly and Rare Disease Registration Service (Public Health England): Congenital anomaly statistics 2018 (PDF, 43 pages)
• 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)
• The Fetal Medicine Foundation: Fetal abnormalities
• World Health Organization: Congenital disorders

For patients

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