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Genetic testing for arrhythmogenic cardiomyopathy (R133)

Arrhythmogenic cardiomyopathy is the broader term that encompasses arrhythmogenic right ventricular cardiomyopathy (ARVC).

Background information

ARVC is characterised by progressive loss and fibro-fatty replacement of the ventricular myocardium. It is associated with ventricular tachycardia and an increased risk of sudden death. However, diagnosis is often difficult because of the non-specific nature of the disorder features and the broad spectrum of phenotypic manifestations.

Currently there are eleven genes on the panel: CDH2, DES, DSC2, DSG2, DSP, FLNC, JUP, PKP2, PLN, TMEM43, and LMNA.

Around a third of clinically confirmed cases have a pathogenic or likely pathogenic variant identified in one of these genes.

PKP2, DSP, DSG2, DSC2, and JUP are desmosomal genes and are established causes of autosomal dominant ARVC. The majority of variants of significance are point variants in PKP2. Large-scale deletions and / or duplications involving this gene are detected in ~2 percent of affected individuals. Pathogenic variants have also been reported in the extra-desmosomal ARVC-associated genes; CDH2, LMNA, PLN, FLNC, DES and TMEM43. Variants in PLN are rare but accounts for 10-15 percent of cases in the Dutch population.

Additional features can be associated with particular genes. FLNC variants are been reported in families with ARVC with additional features including ventricular arrhythmia and sudden cardiac death. Occasionally, individuals with LMNA-related cardiomyopathy also manifest signs or symptoms of skeletal myopathy. There are also recessive forms with additional characteristic features involving the skin and hair. Homozygous or compound heterozygous variants in JUP and DSP cause Naxos disease and Carvajal syndrome.

There a small number of reports of de novo dominantly-acting DSP missense variants detected in individuals with a Carvajal- or Naxos-like phenotype with the accompanying feature of oligodontia (missing teeth). Although rare cases recessive inheritance of DSC2 and DSG2 have been reported. Testing for specific genes within the panel is not available.

Testing strategy

Clinically affected probands:

R133 - Singleton analysis of a small panel of genes. Data from the entire coding region of the main transcripts of DSC2, DSG2, DSP and PKP2 is always included.

Dosage analysis is undertaken by MLPA (using MRC Holland-supplied kit P168) which includes probes for all 14 exons of PKP2 as well as probes for selected exons in DSC2, DSG2, DSP, JUP, RYR2 and TGFB3.

Targeted analysis for known / previously reported familial variants:

Family testing in clinically unaffected family members at risk of inheriting a previously reported familial pathogenic variant (R242)
Diagnostic confirmation in individuals at risk of inheriting a previously reported familial pathogenic variant and clinically suspected of having the familial condition (R240)
Segregation studies in affected family members to aid variant interpretation (R375)
Prenatal diagnosis for families with a pathogenic or likely pathogenic variant identified (R240 and R321 Maternal cell contamination)

Target reporting times

84 calendar days for diagnostic screening of affected individuals

42 calendar days for diagnostic confirmation in individuals at risk of inheriting a previously reported familial pathogenic variant and clinically suspected of having the familial condition (R240)

14 calendar days for presymptomatic testing of clinically unaffected family members at risk of inheriting a previously reported familial pathogenic variant (R242)

Turnaround times for genetic / genomic testing