Nature – To what Extent does Genotype Predict ARVD/C Phenotype?

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Nature – To what Extent does Genotype Predict ARVD/C Phenotype?

Genetic Basis of ARVD/C

Following the landmark discovery in 2000 that mutations in JUP, which encodes plakoglobin, was the cause of Naxos disease,¹² there was rapid discovery of ARVD/C-associated mutations in each of the desmosomal genes including DSP encoding desmoplakin,¹⁸ PKP2 encoding plakophilin-2,¹⁹ DSG2 encoding desmoglein-2²⁰ and DSC2 encoding desmocollin-2.²¹ Cardiac desmosomes are specialised adhesion junctions composed of a symmetrical group of proteins – the cadherins, the armadillo proteins and the plakins – that provide a mechanical connection between cardiac myocytes. It is now known that up to two-thirds of ARVD/C patients have mutations in genes encoding the cardiac desmosome,²² with heterozygous radical mutations in PKP2 most prevalent among the North American and most European populations.^22,23 Inheritance of desmosomal mutations typically follows an autosomal dominant pattern with incomplete penetrance and variable expressivity. However, patients with multiple mutations (compound heterozygosity and digenic) are not uncommon.²⁴ Cases with homozygous mutations and pedigrees more reminiscent of autosomal recessive disease also occur.^25,26 The reported proportion of ARVD/C patients with multiple mutations ranges widely (4–21 %)^23,27 and is likely related to how stringently missense variants are adjudicated.²⁸

Although the vast majority of reported ARVD/C-associated mutations are desmosomal (95.5 % of mutations reported in the ARVD/C Genetic Variant Database),²⁹ extradesmosomal mutations are being identified in an increasing minority of patients. The first of these was a founder mutation in transmembrane protein 43 (TMEM43) S358L discovered among families in Newfoundland, Canada.³⁰ More recently, mutations have been reported in genes previously associated with other cardiomyopathies and arrhythmia syndromes including desmin (DES),³¹ titin (TTN),³² lamin A/C (LMNA),³³ phospholamban (PLN)³⁴ and Na_v1.5 (SCN5A),³⁵ the pore-forming subunit of the voltage-gated cardiac sodium channel. These findings likely reflect clinical overlap of ARVD/C with dilated cardiomyopathy at one phenotypic extreme³⁶ and with arrhythmia syndromes associated with sodium channel dysfunction, particularly Brugada syndrome, at the other.¹⁷ Mutations in the CTNNA3 gene coding for α T-catenin protein in the ‘area composita’, (composed of both desmosomal and adherens junctional proteins), have also recently been shown to be associated with ARVD/C.³⁷ Finally, mutations in transforming growth factor β3 (TGFβ3)³⁸ and the cardiac ryanodine receptor-2 (RYR2)³⁹ have been described, although the association of mutations in these genes with an ARVD/C phenotype have not been confirmed.

The increasing recognition of mutations in extradesmosomal genes among ARVD/C patients is largely the result of advances in geneticsequencing technology (next-generation sequencing). This technology allows for comprehensive sequencing at low cost with rapid turnaround. While identification of mutations in novel ARVD/C genes is useful for both scientific discovery and clinical management, it comes with challenges associated with interpretation of sequence results. As increasing numbers of genes are sequenced in ARVD/C patients, increasing numbers of genetic variants with uncertain pathogenicity are revealed. Missense variants are a significant interpretive challenge. It is important to realise that assessing pathogenicity of genetic variants should be performed with knowledge of the background ‘genetic noise’ in a healthy population. A study by Kapplinger et al.⁴⁰ focusing only on the desmosomal genes highlights the complexity. In this study of 427 putatively healthy individuals, 16 % were found to carry a rare missense variant in the desmosomal genes. (In this study the authors considered each variant exclusively observed in ARVD/C patients but absent in a large, ethnically matched, control cohort a ‘mutation’.) A recently updated ARVD/C-specific genetic variant database (http://www.arvcdatabase.info) encompassing more than 1,400 variants collating published evidence is useful for interpretation.²⁹ Recent recommendations for adjudication of genetic variants suggest increasingly stringent criteria be used.⁴¹

Finally, there remain many ARVD/C cases with no identifiable mutation. In the largest study of ARVD/C families to date, among 439 index cases ascertained through the Johns Hopkins and Dutch Interuniversity Cardiology Institute of the Netherlands (ICIN) ARVD/C Registries, 37 % had no identifiable mutation in the desmosomal genes, PLN or TMEM43.⁷ Of interest, among these cases without mutations, clear evidence of familial disease (meeting ARVD/C 2010 Family History Task Force Criteria)⁴² was present in only one-fifth. This raises the question of whether the remaining 80 % of cases had ARVD/C caused primarily by genetic factors, a question we will return to in the latter part of the paper.