Presentation: Fetus with a brain anomaly

A couple attend their anomaly scan at 19 weeks of pregnancy and are told that there is excess fluid on both sides of their baby’s brain. The baby is diagnosed with moderate ventriculomegaly with a measurement of 14mm. The pregnancy has otherwise been low risk and no associated anomalies have been found so far. A referral is made to the fetal medicine team for further assessment.

• Genomic testing should be considered on the identification of a brain anomaly that is commonly associated with a genetic cause. This includes:
  • cortical malformations;
  • partial or complete agenesis of the corpus collosum;
  • anomalies of the basal ganglia;
  • anomalies of the brain stem;
  • cerebellar anomalies;
  • brain asymmetry with structural anomalies;
  • ventriculomegaly (especially if severe or progressive); and
  • multiple anomalies.
• It is important to exclude other causes, such as infection, wherever possible.

• 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, as further review in a fetal medicine unit is usually warranted. A transvaginal scan may be undertaken to provide better views of the brain. MRI assessment will also be considered.
• A fetal medicine review will determine whether genomic testing is appropriate. The team will also decide which testing is most suitable and/or discuss the case with a multidisciplinary team, depending on the specific clinical scenario and the family’s wishes.
• Referral to clinical genetics is not routinely indicated for isolated ventriculomegaly, though may be relevant if the condition is progressive or associated with other anomalies, in which case fetal exome sequencing may be considered. Other brain anomalies may warrant earlier clinical genetics referral for consideration of detailed genomic testing.
• The genomic tests that could be considered are detailed below;
  • R22 Fetus with a likely chromosomal abnormality. This will process both:
    • • R22.1 Genome-wide common aneuploidy testing; and
      • R22.2 Chromosomal microarray.
  • R21 Fetal anomalies with a likely genetic cause: Fetal exome sequencing.
    • Major central nervous system anomalies, including partial or complete agenesis of the corpus collosum, may meet the eligibility criteria for R21 in isolation. A major exception to this is neural tube defects, which commonly lack a monogenic cause.
    • Mild ventriculomegaly with posterior horn persistently >11mm on ≥ 2 scans requires another anomaly to meet the criteria for R21.
    • Referral to clinical genetics and/or multidisciplinary discussion is required for R21.
  • Where a specific genetic condition is considered likely, or there is a relevant family history, further guided genomic testing may be recommended.
• For R22 you should use your local Genomic Laboratory Hub test order form and consent (record of discussion, or 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 fetal blood sample in an EDTA tube (typically a 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

• International Society of Ultrasound and Gynaecology (ISUOG)
• NHS England: National Genomic Test Directory
• NHS England: The 20-week screening scan
• 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

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)
• SHINE