Presentation: Fetus with orofacial clefts

A pregnant woman with an uncomplicated pregnancy presents at 20 weeks’ gestation for the fetal anomaly scan. The sonographer is unable to see a full and typical outline of the baby’s lips and is therefore suspicious of a cleft lip. The rest of the baby’s anatomy appears normal. The patient is referred to a fetal medicine unit for further review.

• Around 15% of individuals with orofacial clefts have an underlying genetic diagnosis, though the chance of this is dependant on the type of clefting and any associated anomalies. For example:
  • an isolated unilateral cleft is rarely associated with an underlying diagnosis;
  • the chance of an underlying diagnosis is increased with bilateral or midline clefts; and
  • the combination of an orofacial cleft with other associated anomalies may be suggestive of an underlying genetic diagnosis.
• Genomic testing can be considered where an orofacial cleft is identified in combination with other associated anomalies.
• Genomic testing usually includes chromosome testing. Additional testing depends on the associated features or suspected syndromes.

• 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.
• The fetal medicine review will determine whether genomic testing is appropriate, and referral to clinical genetics will be considered. Referral to clinical genetics is not routinely indicated for an isolated facial cleft.
• The fetal medicine team will decide which testing is most suitable and/or discuss the case with a multidisciplinary team, depending on the specific clinical scenario and the pregnant woman’s wishes.
• Depending on the clinical scenario, a range of different genomic tests may be considered.
  • 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.
  • Where there are multiple or complex anomalies:
    • R21 Fetal anomalies with a likely genetic cause. Rapid fetal exome sequencing can be offered if the phenotype is as described above. Unless clinical information and/or initial results indicate otherwise, R21 requests will process:
      • R21.1 Genome-wide common aneuploidy testing;
      • R21.2 Fetal anomalies whole exome sequencing or large panel sequencing; and
      • R21.3 Genome-wide microarray.
  • 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 (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.
• All of the above tests are DNA based and require an amniocentesis or chorionic villus sample or 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

• International Society of Ultrasound in Obstetrics and Gynaecology (ISUOG): Examining the upper lip, face and profile (PDF, 27 pages)
• NHS England: National Genomic Test Directory
• NHS England: 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: Facial cleft

References:

• Kini U. ‘Genetics and orofacial clefts: A clinical perspective‘. British Dental Journal 2023: volume 234, pages 947–952. DOI: 10.1038/s41415-023-5994-3

For patients

• Cleft Lip and Palate Action (CLAPA)
• NHS England: Cleft lip: Information for parents
• NHS Health A to Z: Cleft lip and palate
• NHS North Thames and NHS West Midlands, Oxford and Wessex Genomic Laboratory Hubs: Information on prenatal exome sequencing for parents (PDF, two pages)