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

Giulia Poloni, Martina Calore, Ilaria Rigato, Elena Marras, Giovanni Minervini, Elisa Mazzotti, Alessandra Lorenzon, Ilena Egle Astrid Li Mura, Andrea Telatin, Ivano Zara, Barbara Simionati, Martina Perazzolo Marra, Jessica Ponti, Gianluca Occhi, Libero Vitiello, Luciano Daliento, Gaetano Thiene, Cristina Basso, Domenico Corrado, Silvio TosattoBarbara Bauce, Alessandra Rampazzo*, Marzia De Bortoli

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


BACKGROUND Arrhythmogenic cardiomyopathy (ACM) is associated with arrhythmias and risk of sudden death. Mutations in genes encoding proteins of cardiac intercalated discs account for similar to 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.

Original languageEnglish
Pages (from-to)773-780
Number of pages8
JournalHeart Rhythm
Issue number5
Publication statusPublished - May 2019


  • Arrhythmogenic cardiomyopathy
  • Sudden cardiac death
  • Targeted gene panel
  • TP63 gene
  • PPP1R13L gene
  • P63 GENE
  • P53


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