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 following features:

• 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 hypocalcemia.
• Early puberty.

Note: 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, which provides information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details 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.
• Decide which of the panels best suits the needs of your patient or family. Because 22q11.2 deletion syndrome is caused by a microdeletion at chromosome position 2, you should request a microarray, which will pick up 22q11.2 microdeletions and other chromosomal anomalies.
• For patients with clinical suspicion of 22q11.2 deletion syndrome and congenital heart disease, consider:
  • R137 Congenital heart disease (microarray).
• For patients with clinical suspicion of 22q11.2 deletion syndrome without congenital heart disease, consider:
  • R28 Congenital malformation and dysmorphism syndromes (microarray only).
• For tests that do not include whole genome sequencing (WGS), including R137 and R28:
  • you can use your local Genomic Laboratory Hub 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 ta later date if needed.
• The majority of tests are DNA-based, and an EDTA sample (purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (green-topped tube).
• If microarray testing does not identify 22q11.2 deletion syndrome, consider the possibility of an alternate genetic diagnosis. Options for further testing include:
  • R29.4 Intellectual disability (gene panel sequencing test); and/or
  • R27.3 Paediatric disorders (gene panel sequencing test).
• For tests that are undertaken using WGS, including R29.4 and R27.3, you will need to:
  • complete an NHS GMS test order form with details of the affected child (proband) and parents, 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 WGS for support in completing WGS-specific forms);
  • complete an NHS GMS record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected child 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 a large WGS ‘super panel’ (a panel comprised of several different constituent panels forming one large panel), and requesting it currently requires authorisation from clinical genetics.
• 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, issue 3, page 100,338. 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