R21: Rapid prenatal exome sequencing

Rapid prenatal exome sequencing (R21 in the National Genomic Test Directory) is undertaken for at-risk pregnancies in which a genomic diagnosis would guide management of the fetus. At present, R21 testing may only be requested by a clinical geneticist, usually following multidisciplinary team discussion with the fetal medicine team. Testing requires invasive prenatal sampling and involves exome sequencing of a nationally approved panel of genes known to cause prenatal genetic disorders.

R21 testing can be requested when:

• a fetus presents with multiple anomalies affecting multiple systems; and/or
• the presentation is suggestive of an underlying monogenic disorder; and
• a molecular diagnosis may influence the management of the pregnancy or the baby in the immediate neonatal period.

Some examples of presentations for which R21 testing may be indicated include a fetus with:

• multiple anomalies in a number of different systems;
• a suspected skeletal dysplasia where intrauterine growth restriction has been excluded;
• large echogenic kidneys and a normal bladder;
• major central nervous system anomalies in which a neural tube defect has been excluded;
• multiple contractures (excluding bilateral isolated talipes);
• a nuchal translucency greater than 6.5 millimetres and at least one additional anomaly and in which the array comparative genomic hybridisation (CGH) is normal; and
• non-immune fetal hydrops (fluid/oedema in at least two compartments detected at or after routine second trimester scan) and a normal array CGH.

Please also refer to the test directory for the complete lists of eligibility and exclusion criteria.

R21 testing is undertaken by two of the UK’s Genomic Laboratory Hubs (GLHs): Central and South GLH and North Thames GLH. Before a sample is sent to the designated GLH, all referrals must be:

• reviewed by a local consultant clinical geneticist in consultation with the local obstetric team;
• discussed by the clinical geneticist with the receiving GLH;
• sent to the local or referring GLH, who will forward forms and samples to the receiving GLH; and
• accompanied by a completed R21 test request form, including patient details, clinical indications (such as relevant HPO terms), contact details for the clinical geneticist and fetal medicine clinicians, and accompanied by a completed record of discussion form for each parent.

Trio testing is preferred where invasive prenatal samples are sent alongside parental samples.

R21 requests may also include testing for common aneuploidy testing and microarray, unless determined to be unnecessary. This should be discussed with the designated GLH upon request.

For clinicians

• East Genomics GLH Training: R21 test for fetal anomalies – what to discuss with parents and how to take consent (video, four minutes)
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National genomic test directory
• NHS Genomic Medicine Service: Rapid Exome Sequencing Service for fetal anomalies testing – Frequently Asked Questions (PDF, 5 pages)
• NHS North Thames GLH and West Midlands, Oxford and Wessex GLH: Record of discussion regarding prenatal exome sequencing form (PDF, 2 pages)