Cardiomyopathy genetic testing

Arrhythmogenic cardiomyopathy (ACM)

Arrhythmogenic cardiomyopathy (ACM) is a rare, heritable heart disease characterized by fibro-fatty replacement of the myocardium and a high degree of electric instability. The disease phenotype is highly variable and characterised by incomplete penetrance.[126]

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C; also referred to as AVC), is an important cause of sudden cardiac death (SCD) in young adults. The exact prevalence of ARVD/C is unknown but is estimated at 1:1000 to 1:1250 [34]. The phenotype of ARVD/C is widely variable (even within families) and many patients may be asymptomatic; please refer to the diagnostic criteria for further details [35]. Expression is age-dependent and incomplete penetrance is often observed [1]. ARVD/C is typically inherited in an autosomal dominant manner [34] and most of the genes implicated in ARVC/D, such as PKP2, DSG2, DSP and DSC2 encode desmosomal proteins [28]. There are recessive forms of the disease, such as Naxos disease which are associated with a cutaneous phenotype [35]. The overall yield of genetic testing for all available genes in probands who meet diagnostic criteria approximates 50% [34]. Most described mutations are nucleotide substitutions, insertions or deletions, but one study detected whole exon deletions in the PKP2 gene in 2% of cases [36].

Dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is characterised by ventricular enlargement and systolic dysfunction. The estimated prevalence of idiopathic DCM is between 1:250 and 1:500 individuals [38]. Clinical overlap with other cardiomyopathies (HCM and ARVC) has been described and can lead to diagnostic uncertainty [39]. DCM can demonstrate variable age of onset and penetrance, even within the same family [1]. Pathogenic variants in more than 30 genes are known to account for approximately 40%-50% of familial DCM with autosomal dominant inheritance in most cases [36], although all inheritance patterns have been identified (autosomal recessive, X-linked, and mitochondrial) [30]. Most DCM genes contribute only a small percentage of all pathogenic variants and demonstrate significant locus and allelic heterogeneity, however TTN truncating mutations are a common cause, reported to occur in 14-25% of DCM cases [43] [18]. Numerous syndromes have also been reported in association with DCM, including muscular dystrophies.  

Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy in a non-dilated ventricle. The prevalence is estimated to be 1:500, making HCM one of the most common inherited monogenic cardiovascular diseases. HCM has a variable age of onset, expressivity and incomplete penetrance [41]. In addition, there can be clinical and genetic overlap between HCM and left ventricular non-compaction (LVNC) [28]. A pathogenic variant is expected to be found in around 50% of patients with HCM and a positive family history and in 30% of patients with no family history [41]. Pathogenic variants in the cardiac myosin binding protein C (MYBPC3) and cardiac beta-myosin heavy chain (MYH7) genes are the most common genetic cause, but additional genes encoding other proteins that affect the sarcomere, the contractile unit of cardiac muscle have been implicated [41]. It has been reported that approximately 6% of patients have more than one pathogenic variant and this may be associated with a more severe phenotype [42]. A number of phenocopies of HCM present with apparently similar cardiac features but different inheritance patterns and/or systemic features [28]. Defects in genes involved in storage diseases, such as LAMP2 (Danon disease), GLA (Fabry disease) and PRKAG2 (Wolff-Parkinson-White syndrome) typically cause systemic disease but may also result in predominant cardiac manifestations, which can mimic HCM.

Laminopathy

Noncompaction cardiomyopathy (ncCM/LVNC)

Left ventricular noncompaction (LVNC) is characterized by excessive and unusual trabeculations within the mature left ventricle, but exhibits considerable clinical heterogeneity and may represent the morphological spectrum of many phenotypically distinct cardiomyopathies rather than a single, separate entity [43]. Its exact incidence and prevalence are unknown. LVNC has been linked to pathogenic variants in sarcomeric, cytoskeletal, Z-line, and mitochondrial proteins [43], most commonly  MYH7 and ACTC1 [44], showing different inheritance patterns. The yield of genetic testing in affected patients for LVNC is 40% to 50% [43]. Sporadic cases are common and LVNC is also associated with various syndromes [45], including Barth Syndrome (caused by pathogenic variants in TAZ).    

Fabry disease

Other genes included under all cardiomyopathy

Clinical genetics and genomics laboratory

Ground floor (level 2), Sydney wing, Royal Brompton Hospital, Sydney Street, London, SW3 6NP

Telephone: 020 7352 8121 ext. 83009
Email: rbh-tr.genomics@nhs.net or geneticslab@rbht.nhs.uk
Opening hours: Monday to Friday, 9 am - 5 pm
Head of laboratory: Dr Deborah Morris-Rosendahl

Useful documents

Molecular genetic testing request and consent form (pdf, 431KB)

Non-NHS molecular genetic testing request and consent form (pdf, 493KB)