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A targeted next-generation gene panel reveals a novel heterozygous nonsense variant in the TP63 gene in patients with arrhythmogenic cardiomyopathy

Published:November 16, 2018DOI:https://doi.org/10.1016/j.hrthm.2018.11.015

      Background

      Arrhythmogenic cardiomyopathy (ACM) is associated with arrhythmias and risk of sudden death. Mutations in genes encoding proteins of cardiac intercalated discs account for ∼60% of ACM cases, but the remaining 40% is still genetically elusive.

      Objective

      The purpose of this study was to identify the underlying genetic cause in probands with ACM.

      Methods

      DNA samples from 40 probands with ACM, negative for mutations in the 3 major ACM genes—DSP, PKP2, and DSG2, were screened by using a targeted gene panel consisting of 15 known ACM genes and 53 candidate genes.

      Results

      About half of patients were found to carry rare variant(s) predicted to be damaging; specifically, 9 (22.5%) showed ≥1 variants in genes associated with ACM and/or with other inherited heart diseases and 10 (25%) showed variants in candidate genes. Among the latter, we focused on 2 novel variants in TP63 and PPP1R13L candidate genes (c.796C>T, p.(R266*) and c.1858G>C, p.(A620P), respectively). The encoded proteins p63 and inhibitor of apoptosis stimulating p53 protein are known to be interacting partners. Inhibitor of apoptosis stimulating p53 protein is a shuttling multifunctional protein: in the nucleus it is critical for inhibiting p63 function, whereas in the cytoplasm it regulates desmosome integrity. According to the American College of Medical Genetics and Genomics guidelines, the variant in TP63 has been scored as likely pathogenic and the variant in PPP1R13L as a variant of uncertain significance. Importantly, the mutant TP63 allele leads to nonsense-mediated messenger RNA decay, causing haploinsufficiency.

      Conclusion

      Our findings identify TP63 as a putative novel disease gene for ACM, while the possible involvement of PPP1R13L remains to be determined.

      Keywords

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      References

        • Thiene G.
        • Nava A.
        • Corrado D.
        • Rossi L.
        • Pennelli N.
        Right ventricular cardiomyopathy and sudden death in young people.
        N Engl J Med. 1988; 318: 129-133
        • Basso C.
        • Bauce B.
        • Corrado D.
        • Thiene G.
        Pathophysiology of arrhythmogenic cardiomyopathy.
        Nat Rev Cardiol. 2011; 9: 223-233
        • Poloni G.
        • De Bortoli M.
        • Calore M.
        • Rampazzo A.
        • Lorenzon A.
        Arrhythmogenic right-ventricular cardiomyopathy: molecular genetics into clinical practice in the era of next generation sequencing.
        J Cardiovasc Med (Hagerstown). 2016; 17: 399-407
        • Turkowski K.L.
        • Tester D.J.
        • Bos J.M.
        • Haugaa K.H.
        • Ackerman M.J.
        Whole exome sequencing with genomic triangulation implicates CDH2-encoded N-cadherin as a novel pathogenic substrate for arrhythmogenic cardiomyopathy.
        Congenit Heart Dis. 2017; 12: 226-235
        • Mayosi B.M.
        • Fish M.
        • Shaboodien G.
        • et al.
        Identification of cadherin 2 (CDH2) mutations in arrhythmogenic right ventricular cardiomyopathy.
        Circ Cardiovasc Genet. 2017; 10
        • Calore M.
        • Lorenzon A.
        • De Bortoli M.
        • Poloni G.
        • Rampazzo A.
        Arrhythmogenic cardiomyopathy: a disease of intercalated discs.
        Cell Tissue Res. 2015; 360: 491-500
        • Groeneweg J.A.
        • Bhonsale A.
        • James C.A.
        • et al.
        Clinical presentation, long-term follow-up, and outcomes of 1001 arrhythmogenic right ventricular dysplasia/cardiomyopathy patients and family members.
        Circ Cardiovasc Genet. 2015; 8: 437-446
        • Richards S.
        • Aziz N.
        • Bale S.
        • et al.
        Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
        Genet Med. 2015; 17: 405-424
        • Notari M.
        • Hu Y.
        • Koch S.
        • et al.
        Inhibitor of apoptosis-stimulating protein of p53 (iASPP) prevents senescence and is required for epithelial stratification.
        Proc Natl Acad Sci U S A. 2011; 108: 16645-16650
        • Marras E.
        • Basso C.
        • Sciarra L.
        • Delise P.
        Unexplained syncope, Brugada-like ECG and minimal structural right ventricular abnormalities: which is the right diagnosis?.
        J Cardiovasc Med (Hagerstown). 2009; 10: 273-275
        • Shapiro L.
        • Weis W.I.
        Structure and biochemistry of cadherins and catenins.
        Cold Spring Harb Perspect Biol. 2009; 1: a003053
        • Sethi I.
        • Romano R.A.
        • Gluck C.
        • Smalley K.
        • Vojtesek B.
        • Buck M.J.
        • Sinha S.
        A global analysis of the complex landscape of isoforms and regulatory networks of p63 in human cells and tissues.
        BMC Genomics. 2015; 16: 584
        • Rouleau M.
        • Medawar A.
        • Hamon L.
        • et al.
        TAp63 is important for cardiac differentiation of embryonic stem cells and heart development.
        Stem Cells. 2011; 29: 1672-1683
        • Paris M.
        • Rouleau M.
        • Pucéat M.
        • Aberdam D.
        Regulation of skin aging and heart development by TAp63.
        Cell Death Differ. 2012; 19: 186-193
        • van Bokhoven H.
        • McKeon F.
        Mutations in the p53 homolog p63: allele-specific developmental syndromes in humans.
        Trends Mol Med. 2002; 8: 133-139
        • Carroll D.K.
        • Carroll J.S.
        • Leong C.O.
        • Cheng F.
        • Brown M.
        • Mills A.A.
        • Brugge J.S.
        • Ellisen L.W.
        p63 regulates an adhesion program and cell survival in epithelial cells.
        Nat Cell Biol. 2006; 8: 551-561
        • Ferone G.
        • Mollo M.R.
        • Thomason H.A.
        • Antonini D.
        • Zhou H.
        • Ambrosio R.
        • De Rosa L.
        • Salvatore D.
        • Getsios S.
        • van Bokhoven H.
        • Dixon J.
        • Missero C.
        p63 control of desmosome gene expression and adhesion is compromised in AEC syndrome.
        Hum Mol Genet. 2013; 22: 531-543
        • Valenzise M.
        • Arrigo T.
        • De Luca F.
        • Privitera A.
        • Frigiola A.
        • Carando A.
        • Garelli E.
        • Silengo M.
        R298Q mutation of p63 gene in autosomal dominant ectodermal dysplasia associated with arrhythmogenic right ventricular cardiomyopathy.
        Eur J Med Genet. 2008; 51: 497-500
        • Rinne T.
        • Spadoni E.
        • Kjaer K.W.
        • et al.
        Delineation of the ADULT syndrome phenotype due to arginine 298 mutations of the p63 gene.
        Eur J Hum Genet. 2006; 14: 904-910
        • Rinne T.
        • Clements S.E.
        • Lamme E.
        • et al.
        A novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp-Hodgkin/Hay-Wells-like syndromes.
        Hum Mol Genet. 2008; 17: 1968-1977
        • Basha M.
        • Demeer B.
        • Revencu N.
        • Helaers R.
        • Theys S.
        • Bou Saba S.
        • Boute O.
        • Devauchelle B.
        • Francois G.
        • Bayet B.
        • Vikkula M.
        Whole exome sequencing identifies mutations in 10% of patients with familial non-syndromic cleft lip and/or palate in genes mutated in well-known syndromes.
        J Med Genet. 2018; 55: 449-458
        • Dedeić Z.
        • Sutendra G.
        • Hu Y.
        • Chung K.
        • Slee E.A.
        • White M.J.
        • Zhou F.Y.
        • Goldin R.D.
        • Ferguson D.J.P.
        • McAndrew D.
        • Schneider J.E.
        • Lu X.
        Cell autonomous role of iASPP deficiency in causing cardiocutaneous disorders.
        Cell Death Differ. 2018; 25: 1289-1303
        • Notari M.
        • Hu Y.
        • Sutendra G.
        • et al.
        iASPP, a previously unidentified regulator of desmosomes, prevents arrhythmogenic right ventricular cardiomyopathy (ARVC)-induced sudden death.
        Proc Natl Acad Sci U S A. 2015; 112: e973-e981
        • Chikh A.
        • Matin R.N.
        • Senatore V.
        • et al.
        iASPP/p63 autoregulatory feedback loop is required for the homeostasis of stratified epithelia.
        EMBO J. 2011; 30: 4261-4273
        • Falik-Zaccai T.C.
        • Barsheshet Y.
        • Mandel H.
        • et al.
        Sequence variation in PPP1R13L results in a novel form of cardio-cutaneous syndrome.
        EMBO Mol Med. 2017; 9: 1326
        • Robinson R.A.
        • Lu X.
        • Jones E.Y.
        • Siebold C.
        Biochemical and structural studies of ASPP proteins reveal differential binding to p53, p63, and p73.
        Structure. 2008; 16: 259-268