Presentation: Child with hypertrophic cardiomyopathy

A 10-year-old girl is referred to paediatric cardiology due to the incidental finding of a murmur. An echocardiogram demonstrates asymmetric hypertrophy of the left ventricle (LV). Taking a full family history reveals a significant history of sudden death.

• Consider genomic testing in a child if:
  • the cardiomyopathy has an onset of under 12 years of age without a non-genetic explanation;
  • the individual, of any age, has cardiomyopathy as their primary clinical presentation and there is also a second condition, such as dysmorphism, or other feature(s) suggestive of a syndromic cause such as a RASopathy (for example, Noonan syndrome);
  • the child is 18 years of age with a LV wall thickness more than two standard deviations greater than the predicted mean (z-score >2, where a z-score is defined as the number of standard deviations from the population mean);
  • there is an otherwise unexplained increased LV wall thickness ≥13 mm in one or more LV myocardial segments, in a patient with a first-degree relative with unequivocal disease (LV hypertrophy ≥15mm), and a family member with unequivocal disease is unavailable for testing; or
  • the individual is deceased, with pathologically confirmed hypertrophic cardiomyopathy (HCM), in which case the testing would be conducted for the purpose of post-mortem DNA analysis.

Testing should only be carried out in parallel with expert phenotypic assessment – for example, in an inherited cardiac conditions (ICC) clinical service or a specialist paediatric cardiomyopathy service – and with support from clinical genetics services where appropriate.

• 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.
• If the relevant eligibility criteria are met, discuss the case with or refer it to your local ICC clinical service for genomic testing and family screening. You will need to provide details confirming that the patient fulfils the criteria.
• If the patient fulfils diagnostic criteria as detailed in published guidelines that differ from the eligibility criteria in the test directory, it is appropriate to refer the case to an ICC clinic for further assessment.
• For paediatric cardiomyopathy, there are several available indications, including the below.
  • R131 Hypertrophic cardiomyopathy: This indication investigates single-gene, non-syndromic causes of hypertrophic cardiomyopathy. It includes whole exome sequencing (WES) or medium gene panel sequencing.
  • R135 Paediatric or syndromic cardiomyopathy: This indication typically includes whole genome sequencing (WGS); however, an expedited WES-based pathway is available when clinically necessary.
• In some patients, a specific disease may be strongly suspected (for example, Barth syndrome) and isolated testing may be appropriate.
• For tests that do not include WGS, including R131 and expedited R135, 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 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

• European Society of Cardiology: 2023 ESC Guidelines for the diagnosis and management of hypertrophic cardiomyopathies
• NHS England: National Genomic Test Directory

References:

• Norrish G, Cleary A, Field E and others. ‘Clinical features and natural history of preadolescent nonsyndromic hypertrophic cardiomyopathy’. Journal of the American College of Cardiology 2022: volume 79, issue 20, pages 1,986–1,997. DOI: 10.1016/j.jacc.2022.03.347
• Norrish G, Field E and Kaski JP. ‘Childhood hypertrophic cardiomyopathy: A disease of the cardiac sarcomere’. Frontiers in Pediatrics 2021: volume 9, article number 708679. DOI: 10.3389/fped.2021.708679
• Ommen SR, Mital S, Burke MA and others. ‘2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy’. Circulation 2020: volume 142, issue 25, pages e558–e631. DOI: 10.1161/CIR.0000000000000937

For patients

• British Heart Foundation: Hypertrophic cardiomyopathy (HCM)
• Cardiac Risk in the Young: Hypertrophic cardiomyopathy: Changing the paradigm of exercise prescription and competitive sport participation
• Cardiomyopathy UK: Support and information for parents, caregivers and families
• myheart: Hypertrophic cardiomyopathy (HCM)
• NHS Health A to Z: Cardiomyopathy