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]

Gene name Transcript
DES   ENST00000373960 
DSC2  ENST00000280904 
DSG2  ENST00000261590  
DSP   ENST00000379802 
JUP  ENST00000393930 
LMNA  ENST00000368300 
PKP2  ENST00000070846 
PLN  ENST00000357525 
RBM20  ENST00000369519 
RYR2  ENST00000366574 
SCN5A  ENST00000333535 
TGFB3 ENST00000238682 
TMEM43  ENST00000306077 
TTN  ENST00000589042 

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].

Gene name  Transcript Clinical sensitivity
PKP2 ENST00000070846 10-52% [28,37]
DSG2 ENST00000261590 3-19% [28,37
DSC2 ENST00000280904 1-13% [28,37
DSP ENST00000379802 1-16% [28,37
DES ENST00000373960 n/a
JUP ENST00000393930 n/a
RYR2 ENST00000366574 n/a
TMEM43 ENST00000306077 n/a
FLNC    
PLN    
CDH2    

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.  

Gene name Transcript Clinical sensitivity
TTN ENST00000589042 14.1-20% [39,40]
LMNA ENST00000368300 4.5-6% [39,40]
MYH7 ENST00000355349 4.2-4.9% [39,40]
TPM1 ENST00000403994 1-1.9% [39,40]
TNNT2 ENST00000367318 2.9% [39,40]
RBM20 ENST00000369519 1.9-2.6% [39,40
MYH6 ENST00000356287 3-4% [40
TNNC1 ENST00000232975 1-1.3% [40
SCN5A ENST00000333535

2-4% [39

BAG3 ENST00000369085 2.5% [40
ANKRD1 ENST00000371697 2.2% [40
SGCD ENST00000337851 <1% [40]
LDB3 ENST00000361373 1% [40
TCAP ENST00000309889 1% [40
VCL ENST00000211988 1% [40
DSG2 ENST00000261590 0.8% [40
DSP ENST00000379802 2.4% [39
NEXN ENST00000334785 1.3% [39
DES ENST00000373960 0.5% [39]
PLN ENST00000357525 0.4% [39
ACTC1 ENST00000290378 0.3% [39]
ACTN2 ENST00000366578 0.3% [39
MYBPC3 ENST00000545968 0.3% [39
TNNI3 ENST00000344887 0.3% [39
ABCC9 ENST00000261201 0.2% [39
CSRP3 ENST00000533783 0.2% [39
CRYAB ENST00000526180

n/a

DMD ENST00000357033 n/a
DSC2 ENST00000280904 n/a
EYA4 ENST00000367895 n/a
FKTN ENST00000223528 n/a
GATAD1 ENST00000287957 n/a
JUP ENST00000393930 n/a
LAMP2 ENST00000200639 n/a
MYPN ENST00000358913 n/a
PKP2 ENST00000070846 n/a
PRDM16 ENST00000270722 n/a
TBX20 ENST00000408931 n/a

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.

Gene name Transcript Clinical sensitivity
MYBPC3 ENST00000545968 16.6% [41]
MYH7 ENST00000355349 10.6% [41
TNNI3 ENST0000034887 1.5% [41]
TNNT2 ENST00000367318 1.2% [41]
TPM1 ENST00000403994 0.8% [41]
MYL2 ENST00000228841 0.7% [41] 
ACTC1 ENST00000290378 n/a
ACTN2 ENST00000366578 n/a
ANKRD1 ENST00000371697 n/a
CRYAB ENST00000526180 n/a
CSRP3 ENST00000533783 n/a
CAV3 ENST00000343849 n/a
FHL1 ENST00000370690 n/a
GAA ENST00000302262 n/a
LAMP2 ENST00000200639 n/a
GLA ENST00000218516 n/a
JPH2 ENST00000372890 n/a
LDB3 ENST00000361373 n/a
MYH6 ENST00000356287 n/a
MYPN ENST00000358913 n/a
MYL3 ENST00000395869 n/a
MYLK2 ENST00000375994 n/a
MYOZ2 ENST00000307128 n/a
NEXN ENST00000334785 n/a
PLN ENST00000357525 n/a
PRKAG2 ENST00000287878 n/a
TCAP ENST00000309889 n/a
TNNC1 ENST00000232975 n/a
TTR ENST00000237014 n/a
FLNC n/a  

Laminopathy

Gene name Transcript Clinical sensitivity
LMNA ENST00000368300  

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).    

Gene name Transcript Clinical sensitivity
MYH7 ENST00000355349 22% [44]
ACTC1  ENST00000290378  20% [44] 
TAZ  ENST00000299328  19% [44] 
MYBPC3  ENST00000545968  3% [44] 
TNNT2  ENST00000367318  1% [44] 
MIB1  ENST00000261537  n/a 
PRDM16  ENST00000270722  n/a 
TPM1 ENST00000403994  n/a 

Fabry disease

Gene name Transcript Clinical sensitivity
GLA ENST00000218516  

Other genes included under all cardiomyopathy

Gene name

Transcript

Gene name

Transcript

ACTA1

ENST00000366684

LAMA4

ENST00000424408

ALMS1

ENST00000264448

MAP2K1

ENST00000307102

CALR3

ENST00000269881

MAP2K2

ENST00000262948

CASQ2

ENST00000261448

MURC

ENST00000307584

COX15

ENST00000370483

NDUFB11

 

DNAJC19

ENST00000382564

NPPA

ENST00000376480

DOLK

ENST00000372586

NRAS

ENST00000369535

DTNA

ENST00000348997

PDLIM3

ENST00000284770

EMD

ENST00000369842

PNPLA2

 

FKRP

ENST00000391909

PTPN11

ENST00000351677

FXN

ENST00000377270

RIT1

 

GATA4

Na

SDHA

ENST00000264932

GATA5

Na

SGCB

ENST00000381431

GATA6

na

SGCG

ENST00000218867

HADHA

ENST00000380649

SHOC2

ENST00000369452

HFE

ENST00000357618

SLC25A4

ENST00000281456

HRAS

ENST00000311189

SOS1

ENST00000426016

ILK

ENST00000299421

TBX1

 

KLF10

ENST00000285407

TGFB3

ENST00000238682

KRAS

ENST00000311936

TMPO

ENST00000266732

LAMA2

ENST00000421865

TXNRD2

ENST00000400521

 


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)

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