Presentation: Adult with hypertrophic cardiomyopathy 

A 45-year-old man is referred for clinical assessment due to chest pain and shortness of breath on exertion. He also mentions having sporadic palpitations, but denies having had any syncopal events. On examination, he has a systolic murmur, which is more audible at the apex/left sternal edge and gets louder when the Valsalva manoeuvre is performed. Cardiac imaging suggests obstructive hypertrophic cardiomyopathy (HCM). He has two children and three siblings, and both his parents are alive.

• Genomic testing is recommended in adults who have:
  • a clinical diagnosis of HCM meeting the National Genomic Test Directory eligibility criteria listed below; and
  • relatives who would benefit from cascade testing using a genetic diagnosis.
• The test directory eligibility criteria require a firm clinical diagnosis of hypertrophic cardiomyopathy as indicated by:
  • an adult with wall thickness of ≥15mm in one or more left ventricular (LV) myocardial segments that is not explained solely by loading conditions (principally hypertension), with age of onset below 60 years;
  • otherwise unexplained increased LV wall thickness of ≥13mm in one or more LV myocardial segments, if the patient has a first-degree relative with unequivocal disease (LV hypertrophy of ≥15mm), where a family member with unequivocal disease is unavailable for testing; or
  • a deceased individual with pathologically confirmed hypertrophic cardiomyopathy for post-mortem DNA analysis.
• A clinical diagnosis of hypertrophic cardiomyopathy can also be made in an adult who meets the following criteria, which are not listed in the test directory:
  • wall thickness of ≥15 mm in one or more LV myocardial segments that is not explained solely by loading conditions, with or without asymmetric hypertrophy and a ratio of maximal septal-to-corresponding lateral or apical-to-posterior wall thickness of ≥1.3mm or >1.5mm if the patient is hypertensive; or
  • loss of the usual apical wall thickness tapering due to its thickness exceeding basal wall thickness, although failing to reach the apical hypertrophic cardiomyopathy diagnostic wall thickness cut-off of ≥15 mm, with spade‐like configuration and apical obliteration.
• Genomic testing can also be considered if diagnosis would change the treatment plan (including whether relatives would be offered testing) in the event of hypertrophic cardiomyopathy phenocopies (such as transthyretin amyloidosis and Fabry disease) being suspected.
• Testing should be carried out in parallel with expert phenotypic assessment – for example in an inherited cardiac conditions (ICC) clinic – and with support from clinical genetics services where appropriate. Note that testing may occasionally be appropriate outside these criteria following a discussion in an ICC multidisciplinary team meeting.

• 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.
• The relevant clinical indication for adults (or teenagers) with hypertrophic cardiomyopathy is:
  • R131 Hypertrophic cardiomyopathy. This indication investigates single-gene causes of hypertrophic cardiomyopathy and includes whole exome sequencing or medium gene panel sequencing.
• The relevant clinical indication for younger patients (with onset <12 years of age) with unexplained cardiomyopathy, or for individuals of any age in whom a syndromic diagnosis is considered, is:
  • R135 Paediatric or syndromic cardiomyopathy. This indication includes whole genome sequencing (WGS).
• Consider mimics of hypertrophic cardiomyopathy if there is strong clinical suspicion of familial amyloidosis or neuromuscular, mitochondrial, metabolic or malformation syndromes. In these conditions, LV hypertrophy appears in association with other features.
• – 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, or RoD) forms; and
  • note that, when testing in children, parental samples may be helpful for interpretation of the proband’s result. Parental samples can be taken alongside that of the proband, 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 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
  • note that, when testing in children, you should 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 management of cardiomyopathies
• NHS England: National Genomic Test Directory

References:

• Hughes RK, Knott KD, Malcolmson J and others. ‘Apical hypertrophic cardiomyopathy: The variant less known’. Journal of the American Heart Association 2020: volume 9, issue 5, page e015294. DOI: 10.1161/JAHA.119.015294
• Ommen SR, Mital S, Burke MA and others. ‘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: Hypertropic cardiomyopathy
• Cardiac Risk in the Young: Hypertrophic cardiomyopathy?
• Cardiomyopathy UK
• myheart: Hypertrophic cardiomyopathy
• NHS Health A to Z: Cardiomyopathy