A combinatorial oligogenic basis for the phenotypic plasticity between late-onset dilated and arrhythmogenic cardiomyopathy in a single family

Abstract

Introduction: Primary dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) are the two common and distinct forms of hereditary cardiomyopathies caused by defined pathogenic variants (PVs) typically in different sets of genes. DCM is characterized by left ventricular dilatation, dysfunction, and failure, whereas ARVC classically involves the right ventricle and is characterized by fibrofatty infiltration of the myocardium. DCM is caused primarily by the PVs in genes encoding sarcomere and cytoskeletal protein, while ARVC is mainly a disease of the desmosome proteins. DCM and ARVC exhibit partial phenotypic and genetic overlaps.

Aim: To analyze the genetic basis of the phenotypic heterogeneity of cardiomyopathy in members of a single family.

Methods and Results: We recruited, clinically characterized, and performed whole-exome sequencing in five affected, three probably affected, and two clinically unaffected members of a single family. The family members mainly exhibited late-onset DCM associated with conduction defects and arrhythmias. One family member who died suddenly was diagnosed with the classic ARVC at autopsy and another presented with isolated ventricular tachycardia. A novel splicing (truncating) and a rare missense variant in the TTN gene, likely in cis, co-segregated with the phenotype in all affected and probably affected family members and were likely the causal variants. Several PVs and LPVs in other genes involved in cardiomyopathies and arrhythmias were also identified that seem to modify the expression of the phenotype. Notably, LPVs in the DSP and PKP2 genes, which are known genes for ARVC, were identified in the family member who also carried the TTN variants but developed the classic ARVC.

Conclusion: The findings indicate the causal role of the TTN variants, exhibiting an age-dependent penetrance in late-onset DCM, and highlight the potential modifying role of the concomitant LPVs in additional genes on the expression of the phenotype, including a phenotypic switch from the anticipated DCM to ARVC. The findings support an oligogenic basis of the cardiac phenotype in hereditary cardiomyopathies. A comprehensive genetic analysis involving all PVs and LPVs along with detailed phenotypic characterization is necessary to gain insights into the molecular pathogenesis of hereditary cardiomyopathies.

Keywords

Titin / plakophilin 2 / desmoplakin / dilated cardiomyopathy / arrhythmogenic right ventricular cardiomyopathy / genetic / pathogenic variant / sudden death / mutation

References

[1] Marian AJ.Molecular genetic basis of hypertrophic cardiomyopathy.Circ Res2021;128:1533-53 PMCID:PMC8127615

[2] McNally EM.Dilated cardiomyopathy: genetic determinants and mechanisms.Circ Res2017;121:731-48 PMCID:PMC5626020

[3] Corrado D,Judge DP.Arrhythmogenic cardiomyopathy.Circ Res2017;121:784-802

[4] Corrado D,Calkins H.Arrhythmogenic right ventricular cardiomyopathy.N Engl J Med2017;376:61-72

[5] Herman DS,Taylor MR.Truncations of titin causing dilated cardiomyopathy.N Engl J Med2012;366:619-28 PMCID:PMC3660031

[6] Smith ED,Papoutsidakis N.Desmoplakin cardiomyopathy, a fibrotic and inflammatory form of cardiomyopathy distinct from typical dilated or arrhythmogenic right ventricular cardiomyopathy.Circulation2020;141:1872-84 PMCID:PMC7286080

[7] Norman M,Mogensen J.Novel mutation in desmoplakin causes arrhythmogenic left ventricular cardiomyopathy.Circulation2005;112:636-42

[8] Li L,Tan Y,Marian AJ.A potential oligogenic etiology of hypertrophic cardiomyopathy: a classic single-gene disorder.Circ Res2017;120:1084-90 PMCID:PMC5380229

[9] Van der Auwera GA,Hartl C.From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline.Curr Protoc Bioinformatics2013;43:11.10.1-11.10.33 PMCID:PMC4243306

[10] Chen X.Planning bioinformatics workflows using an expert system.Bioinformatics2017;33:1210-5 PMCID:PMC5860174

[11] Auton A,Durbin RM.1000 Genomes Project ConsortiumA global reference for human genetic variation.Nature2015;526:68-74 PMCID:PMC4750478

[12] Wang K,Hakonarson H.ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data.Nucleic Acids Res2010;38:e164 PMCID:PMC2938201

[13] Guo W,Greaser ML.RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing.Nat Med2012;18:766-73 PMCID:PMC3569865

[14] Lim D,Marian AJ.Expression profiling of cardiac genes in human hypertrophic cardiomyopathy: insight into the pathogenesis of phenotypes.J Am Coll Cardiol2001;38:1175-80 PMCID:PMC2776821

[15] Tsubata S,Vatta M.Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy.J Clin Invest2000;106:655-62 PMCID:PMC381284

[16] Chen L,Tester DJ,Ackerman MJ.Mutation of an A-kinase-anchoring protein causes long-QT syndrome.Proc Natl Acad Sci U S A2007;104:20990-5 PMCID:PMC2409254

[17] Chambers JC,Terracciano CM.Genetic variation in SCN10A influences cardiac conduction.Nat Genet2010;42:149-52

[18] Gerull B,Wichter T.Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy.Nat Genet2004;36:1162-4

[19] Rampazzo A,Malacrida S.Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy.Am J Hum Genet2002;71:1200-6 PMCID:PMC385098

[20] Taylor M,Sinagra G.Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes.Circulation2011;124:876-85 PMCID:PMC3167235

[21] Marian AJ.Clinical interpretation and management of genetic variants.JACC Basic Transl Sci2020;5:1029-42 PMCID:PMC7591931

[22] Choi SH,Roselli C.DiscovEHR study and the NHLBI trans-omics for precision medicine (TOPMed) consortiumAssociation between titin loss-of-function variants and early-onset atrial fibrillation.JAMA2018;320:2354-64 PMCID:PMC6436530

[23] Xiao L,Sun Y.Clinical significance of variants in the TTN gene in a large cohort of patients with sporadic dilated cardiomyopathy.Front Cardiovasc Med2021;8:657689 PMCID:PMC8120103

[24] Hu D,Terzic A.ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene.Int J Cardiol2014;171:431-42 PMCID:PMC3947869

[25] Mohler PJ,Gramolini AO.Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death.Nature2003;421:634-9

[26] Marian AJ.Nature's genetic gradients and the clinical phenotype.Circ Cardiovasc Genet2009;2:537-9 PMCID:PMC2908306

[27] Marian AJ.Causality in genetics: the gradient of genetic effects and back to Koch's postulates of causality.Circ Res2014;114:e18-21 PMCID:PMC3896867