Presentation: Teenager with cardiomyopathy

A 15-year-old girl is referred to paediatric cardiology due to the incidental finding of a murmur. She is generally well and excels at school. An echocardiogram demonstrates asymmetric hypertrophy of the left ventricle. Taking a full family medical history reveals a significant history of sudden death.

• Consider genomic testing if the patient is under 18 years old and their left ventricle wall thickness is more than two standard deviations (2SD) above the predicted population mean (in other words, the z-score, which is defined as the number of standard deviations from the population mean, is above two).
• 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 services where appropriate. Note that testing may occasionally be appropriate outside these criteria following discussion at an ICC multidisciplinary team meeting.
• Note that you should consider genomic testing in an individual of any age with cardiomyopathy and additional features suggestive of a syndromic cause.

• 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.
• For typical non-syndromic cardiomyopathy features, the relevant clinical indication is:
  • R131 Hypertrophic cardiomyopathy. This indication comprises whole exome sequencing or gene panel sequencing.
• For typical syndromic cardiomyopathy features, the relevant clinical indication is:
  • R135 Paediatric or syndromic cardiomyopathy. This indication investigates cases in which cardiomyopathy is a primary presentation (at any age) and there is a second condition, such as dysmorphism, or other feature(s) suggestive of a syndromic cause such as a RASopathy (for example, Noonan syndrome). The panel uses whole genome sequencing (WGS).
• R240 Diagnostic testing for known mutation(s): This indication should be requested for patients with a family history of cardiomyopathy and a known familial variant, where the patient’s phenotype is in keeping with the familial diagnosis. Consider broader testing if the patient’s phenotype is out of keeping with the family history (for example, there is a significantly earlier onset). The panel involves targeted variant testing.
• In some patients, a specific disease may be strongly suspected and isolated testing may be appropriate.
• The majority of genomic tests for ICCs (including R131) are currently undertaken on a singleton basis, though samples may be needed from additional family members in order to interpret results.
• For tests that are undertaken using WGS (including R135), parental samples should be submitted alongside the patient sample (this is called trio testing). If this is not possible, for example because the child is in care or one or both parents are unavailable for testing, the proband may be tested as a singleton.
• Clinicians within the ICC service who are requesting testing will need to do the following.
  • For tests that do not include WGS, including R131:
    • you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) forms.
  • 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); and
    • 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).
• 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
• European Society of Cardiology: 2023 ESC guidelines for the management of cardiomyopathies

References:

• Marston NA, Han L, Olivotto I and others. ‘Clinical characteristics and outcomes in childhood-onset hypertrophic cardiomyopathy’. European Heart Journal 2021: volume 42, issue 20, pages 1,988–1,996. DOI: 10.1093/eurheartj/ehab148
• 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
• Cardiac Risk in the Young: Hypertrophic cardiomyopathy
• Cardiomyopathy UK: Information for parents, caregivers and families
• NHS Health A to Z: Cardiomyopathy