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 is increased with bilateral or midline clefts.
  • the combination of other associated anomalies may suggestive an underlying genetic syndrome.
• Genomic testing can be considered where an orofacial cleft is identified in combination with other associated anomalies.
• Genomic testing usually includes chromosome testing and additional genomic testing depends on the associated features or suspected syndromes.

• Consult the National Genomic Test Directory. From this directory 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 our dedicated Knowledge Hub resource.
• To find out which genes 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.
• 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 for the patient and/or discuss the case with a multidisciplinary team, depending on the specific clinical scenario and the patient’s wishes.
• Depending on the clinical scenario, a range of different genomic tests may be considered:
  • Where there is an isolated abnormality:
    • 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: 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.
      • A record of discussion (RoD) form is required for fetal exome sequencing.
  • Where a specific genetic condition is considered likely or there is a relevant family history, further guided genomic testing my be recommended.
• For tests that are undertaken using whole genome sequencing (WGS), you will need to:
  • complete an NHS GMS test order form with details of the proband and parents. Include details of the phenotype (refer to human phenotype ontology (HPO) terms or the clinical summary) and the appropriate panel name(s) with associated R number (see How to complete a test order form for WGS for support).
  • complete an NHS GMS RoD form for each person being tested. Note that, if you are undertaking trio testing of an affected child and their parents, you will need three of these forms. (see How to complete a record of discussion form for support).
  • parental samples should be submitted alongside the child’s sample. This is called trio testing. If this is not possible, such as when testing a child in care or a parent is unavailable for testing, the child may be tested as a singleton.
• For tests that do not include WGS, you will need to:
  • complete a test order form and consent (record of discussion) form, available from your local Genomic Laboratory Hub (GLH).
  • include details of the phenotype in the test order form (refer to HPO terms or the clinical summary) as well as the appropriate panel name(s) with associated R number.
  • 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.
• 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 many of the tests (particularly whole genome and exome sequencing), parental samples are also needed or are helpful.
• 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

• Fetal Medicine Foundation: Facial cleft
• Genomics England: Genomic Medicine Service Signed Off Panels Resource
• 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 and eligibility criteria
• NHS England: The 20-week screening scan

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 Association
• NHS England: Cleft lip: information for parents
• NHS Health A to Z: Cleft lip and palate