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. 2022 Sep;43(9):1333-1342.
doi: 10.1002/humu.24436. Epub 2022 Jul 23.

Burden of rare variants in arrhythmogenic cardiomyopathy with right dominant form-associated genes provides new insights for molecular diagnosis and clinical management

Adeline Goudal  1   2 , Matilde Karakachoff  2   3 , Pierre Lindenbaum  2 , Estelle Baron  2 , Stéphanie Bonnaud  4 , Florence Kyndt  5 , Marine Arnaud  5 , Damien Minois  5 , Emmanuelle Bourcereau  5 , Aurélie Thollet  5 , Jean-François Deleuze  6 , Emmanuelle Genin  7 , François Wiart  8 , Jean-Luc Pasquié  9 , Vincent Galand  10 , Frédéric Sacher  11 , Christian Dina  2 , Richard Redon  5 , Stéphane Bezieau  1   5 , Jean-Jacques Schott  5 , Vincent Probst  5 , Julien Barc  2
Affiliations

Burden of rare variants in arrhythmogenic cardiomyopathy with right dominant form-associated genes provides new insights for molecular diagnosis and clinical management

Adeline Goudal et al. Hum Mutat. 2022 Sep.

Abstract

Arrhythmogenic cardiomyopathy with right dominant form (ACR) is a rare heritable cardiac cardiomyopathy disorder associated with sudden cardiac death. Pathogenic variants (PVs) in desmosomal genes have been causally related to ACR in 40% of cases. Other genes encoding nondesmosomal proteins have been described in ACR, but their contribution in this pathology is still debated. A panel of 71 genes associated with inherited cardiopathies was screened in an ACR population of 172 probands and 856 individuals from the general population. PVs and uncertain significance variants (VUS) have been identified in 36% and 18.6% of patients, respectively. Among the cardiopathy-associated genes, burden tests show a significant enrichment in PV and VUS only for desmosomal genes PKP2 (plakophilin-2), DSP (desmoplakin), DSC2 (desmocollin-2), and DSG2 (desmoglein-2). Importantly, VUS may account for 15% of ACR cases and should then be considered for molecular diagnosis. Among the other genes, no evidence of enrichment was detected, suggesting an extreme caution in the interpretation of these genetic variations without associated functional or segregation data. Genotype-phenotype correlation points to (1) a more severe and earlier onset of the disease in PV and VUS carriers, underlying the importance to carry out presymptomatic diagnosis in relatives and (2) to a more prevalent left ventricular dysfunction in DSP variant carriers.

Keywords: arrhythmogenic cardiomyopathy; burden tests; molecular diagnosis; next-generation sequencing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Prevalence of genes involved in ACR in patient set according to the class of pathogenicity of variants. Gray: Patients with a negative genotype; blue: patients with PV or LPV; pink: patients with VUS. ACR, arrhythmogenic cardiomyopathy with right dominant form; LPV, likely pathogenic variants; PV, pathogenic variants; VUS, uncertain significance variants.
Figure 2
Figure 2
Ratio of the percentage of patients with uncertain significance variants (VUS)/percentage of controls with VUS by genes. PKP2, DSG2, and DSC2 are significantly enriched in VUS in arrhythmogenic cardiomyopathy with right dominant form cases compared to controls.
Figure 3
Figure 3
Population proportion according to the age of diagnosis and the presence and the class of variants. Gray: Patients with a negative genotype; blue: patients with PV or LPV; pink: patients with VUS. ACR, arrhythmogenic cardiomyopathy with right dominant form; LPV, likely pathogenic variants; PV, pathogenic variants; VUS, uncertain significance variants.
See this image and copyright information in PMC

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