Presentation: Child with non-syndromic hearing loss

You see a three-year-old child with speech delay in clinic, accompanied by their parents. The child is otherwise fit and healthy, with normal gestation, birth and medical history. You perform a thorough physical and neurological examination, the findings of which are normal. You request an audiological assessment, and the results from the audiogram reveal bilateral sensorineural deafness.

Genomic testing should be considered in cases of:

• confirmed bilateral non-syndromic hearing loss with a possible monogenic cause (that is, likely to be due to a single gene, with no alternate explanation);
• confirmed unilateral non-syndromic hearing loss, if there is also a family history of bilateral or unilateral hearing loss consistent with a monogenic cause (often suggested by audiograms);
• possible milder syndromic conditions in those initially thought to have non-syndromic hearing loss but where careful examination reveals subtle signs suggestive of a broader diagnosis, including:
  • patches of white hair or skin and/or different colour eyes (suggestive of Waardenburg syndrome),
  • facial asymmetry and/or coloboma (suggestive of CHARGE syndrome)
  • preauricular pits or tags and/or branchial cysts/fistulae (suggestive of branchio-oto-renal syndrome).

• 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.
• 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. For non-syndromic hearing loss, this will typically be:
  • R67 Monogenic hearing loss: whole exome sequencing or large panel.
• If wider neurodevelopmental, growth or health concerns become apparent, broader genetic testing through whole genome sequencing incorporating relevant panels may be more appropriate.
  • R27 Paediatric disorders: This would be more suitable for those with hearing loss with multisystem involvement and/or distinctive features.
• R27 is an amalgamation of over 10 panels of genes (including R67) 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 tests that do not include WGS, including R67, you will need to:
  • 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.
• For tests that are undertaken using WGS, including R27, you will need to:
  • complete an NHS GMS 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 WGS for support in completing WGS-specific forms);
  • complete an NHS GMS 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).
• 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

• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• Medline Plus: Non-syndromic hearing loss
• NHS England: National Genomic Test Directory

References:

• del Castillo I, Morín M, Domínguez-Ruiz M and others. ‘Genetic etiology of non-syndromic hearing loss in Europe’. Human Genetics 2022: volume 141, pages 683–696. DOI: 1007/s00439-021-02425-6
• Wang J, Xiang J, Chen L and others. ‘Molecular diagnosis of non-syndromic hearing loss patients using a stepwise approach’. Scientific Reports 2021: volume 11, article 4,036. DOI: 10.1038/s41598-021-83493-6

For patients

• Centers for Disease Control and Prevention: A parent’s guide to genetics and hearing loss (USA-based resource)
• National Deaf Children’s Society: Causes, types and signs of deafness