Presentation: Clinical suspicion of 22q11.2 deletion syndrome

You review a newborn with tetralogy of Fallot, a submucosal cleft palate and hypocalcaemia. This combination of clinical features raises a suspicion of 22q11.2 deletion syndrome.

Consider genomic testing for 22q11.2 deletion syndrome in individuals with:

• tetralogy of Fallot;
• interrupted aortic arch;
• truncus arteriosus; or
• other forms of congenital heart disease and/or disorder of calcium homeostasis.

While the cardiac abnormalities listed above are characteristic of 22q11.2 deletion syndrome, a third of affected individuals do not have congenital heart disease (CHD). You may wish to test for 22q11.2 deletion syndrome in the absence of CHD if a child presents with some of the features listed below.

• Palatal abnormalities: including velopharyngeal insufficiency, cleft palate (typically submucosal), bifid uvula, hypernasal speech and dysphagia.
• Genitourinary anomalies: including renal agenesis, multicystic dysplastic kidneys, hydronephrosis and vesicoureteric reflux.
• Frequent infections/immune deficiency: due to thymic hypoplasia and subsequent impaired T-cell production; this also leads to a predisposition to autoimmune conditions.
• Facial features: including hooded eyelids, flat nasal bridge, bulbous nasal tip, ear abnormalities, micrognathia, asymmetric crying facies and craniosynostosis.
• Gastrointestinal anomalies: including hernias or constipation (with or without a structural cause).
• Developmental (particularly speech) delay and/or learning difficulties.
• Hypoparathyroidism and hypocalcaemia.
• Early puberty.

Note that features of 22q11.2 deletion syndrome can be highly variable, even between members of the same family. It is not uncommon to diagnose 22q11.2 syndrome in a child, then discover that they have inherited it from a (relatively) unaffected parent.

• 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.
• Decide which of the panels best suits the needs of your patient or family.
  • R137 Congenital heart disease – microarray: Consider this for patients with clinical suspicion of 22q11.2 deletion syndrome and congenital heart disease.
  • R28 Congenital malformation and dysmorphism syndromes – microarray only: Consider this for patients with clinical suspicion of 22q11.2 deletion syndrome without congenital heart disease. Where possible, the chromosomal disorder suspected should be specified on the test request form.
• If microarray testing does not identify 22q11.2 deletion syndrome, consider the possibility of an alternate genetic diagnosis. Options for further testing include:
  • R27 Paediatric disorders: This should be considered if there is developmental delay or intellectual disability in association with congenital malformation or overgrowth, and you would like to investigate chromosomal and single-gene causes; or
  • R29 Intellectual disability: This should be considered if a child has global developmental delay or significant intellectual disability in the absence of congenital malformations or overgrowth, and you feel a monogenic cause is likely
• For tests that are undertaken using whole genome sequencing (WGS), including R29.4 and R27.3, you will need to:
  • complete an NHS Genomic Medicine Service test order form with details of the affected individual (proband) and their parents where available, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see How to complete a test order form for whole genome sequencing for support in completing WGS-specific forms); and
  • complete an NHS Genomic Medicine Service record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected individual and their parents, you will need three RoD forms (see How to complete a record of discussion form for support); and
  • submit parental samples alongside the child’s sample (this is trio testing) to aid interpretation, especially for the larger WGS panels (where this is not possible, for example because the child is in care or the parents are unavailable for testing, the child may be submitted as a singleton).
• R27 is an amalgamation of more than 10 panels of genes known to be associated with a broad range of paediatric developmental disorders. It may now be ordered directly by paediatricians, though a discussion with clinical genetics services may be beneficial for some patients.
• For tests that do not include WGS, including R137 and R28:
  • you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) forms; and
  • 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.
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. There are a few tests for which a different type of tube is used; 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

• 22q11.2 Society
• GeneReviews: 22q11.2 deletion syndrome
• Genetic and Rare Diseases Information Center: 22q11.2 deletion syndrome
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory

References:

• Óskarsdóttir S, Boot E, Crowley TB and others. ‘Updated clinical practice recommendations for managing children with 22q11.2 deletion syndrome‘. Genetics in Medicine 2023: volume 25, page 100338. DOI: https://doi.org/10.1016/j.gim.2022.11.006

For patients

• International 22q11.2 Foundation
• Max Appeal (UK patient support group)
• NHS England: Whole genome sequencing patient information leaflets