Presentation: Child with syndromic cardiomyopathy

A 13-year-old boy with a background of mild global developmental delay is referred to paediatric cardiology with a murmur. He has some dysmorphic features and is found to have an atrial septal defect and hypertrophic cardiomyopathy.

• You should consider genomic testing in a child with cardiomyopathy if:
  • the cardiomyopathy has an onset of under 12 years of age without a non-genetic explanation; or
  • the cardiomyopathy is the primary clinical presentation in an individual of any age and there is also a second condition, such as dysmorphism, or other feature(s) suggestive of a syndromic cause such as a RASopathy.
• Testing should be carried out in parallel with expert phenotypic assessment – for example, in an inherited cardiac conditions (ICC) clinic or specialist paediatric cardiology service – and with support from clinical genetics. Note that testing may occasionally be appropriate outside these criteria following a discussion in an ICC multidisciplinary team meeting.
• Expedited testing can be requested if it has the potential to provide an immediate change to treatment for (or clinical management of) the patient – for instance, if it will inform a decision about cardiac transplant, therapeutic intervention or prenatal testing for an ongoing at-risk pregnancy.

• 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 on the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• If eligibility criteria are met, discuss with/refer to your local ICC clinical service for genomic testing and family screening, including details of confirmation that the patient fulfils the criteria.
• If the patient fulfils diagnostic criteria as detailed in other published guidelines, but these guidelines differ to the eligibility criteria in the test directory, it is appropriate to refer to an ICC clinic for further assessment.
• The relevant clinical indications for paediatric cardiomyopathy include the below.
  • R135 Paediatric or syndromic cardiomyopathy: This indication can be completed via whole genome sequencing (WGS) or whole exome sequencing (WES), a decision that will be made by the laboratory.
  • R27 Paediatric disorders: Consider this indication if cardiomyopathy is one of multiple features of a likely multi-system condition. R27 is an amalgamation of over 10 panels of genes known to be associated with a broad range of paediatric developmental conditions. It may now be ordered directly by paediatricians, though a discussion with clinical genetics services may be beneficial. R135 should be requested in addition to R27 to ensure all genes included in R135 are analysed.
• If an urgent result is required to inform management, consider:
  • R14 Acutely unwell children with a likely monogenic disorder; or
  • R135 Paediatric or syndromic cardiomyopathy (semi-rapid).
  • Consider R14 instead of semi-rapid R135 in cases in which cardiomyopathy is part of a more complex presentation or the clinical presentation is highly suggestive of a fully penetrant monogenic condition.
• Note that R135 may be undertaken using either WGS or WES, so check the appropriate procedure with your local laboratory.
• For tests that do not include WGS, including (sometimes) R135:
  • 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 R14, R27 and (sometimes) R135, 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 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 RoD form for support); and
  • submit parental samples alongside the child’s sample 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

• NHS England: National Genomic Test Directory

References:

• Monda E, Rubino M, Lioncino M and others. ‘Hypertrophic cardiomyopathy in children: pathophysiology, diagnosis, and treatment of non-sarcomeric causes’. Frontiers in Pediatrics 2021: volume 9, article number 632293. DOI: 10.3389/fped.2021.632293

For patients

• British Heart Foundation: Hypertropic cardiomyopathy
• Cardiomyopathy UK: Cardiomyopathy in children and young people (PDF, 44 pages)
• Cardiomyopathy UK: Information for parents, caregivers and families
• NHS Health A to Z: Cardiomyopathy