TY - JOUR
T1 - A targeted next-generation gene panel reveals a novel heterozygous nonsense variant in the TP63 gene in patients with arrhythmogenic cardiomyopathy
AU - Poloni, Giulia
AU - Calore, Martina
AU - Rigato, Ilaria
AU - Marras, Elena
AU - Minervini, Giovanni
AU - Mazzotti, Elisa
AU - Lorenzon, Alessandra
AU - Li Mura, Ilena Egle Astrid
AU - Telatin, Andrea
AU - Zara, Ivano
AU - Simionati, Barbara
AU - Marra, Martina Perazzolo
AU - Ponti, Jessica
AU - Occhi, Gianluca
AU - Vitiello, Libero
AU - Daliento, Luciano
AU - Thiene, Gaetano
AU - Basso, Cristina
AU - Corrado, Domenico
AU - Tosatto, Silvio
AU - Bauce, Barbara
AU - Rampazzo, Alessandra
AU - De Bortoli, Marzia
N1 - Funding Information:
This study was supported by the TRANSAC Strategic Research Grant CPDA133979/13, University of Padua, Italy; Target Projects 331/12, RP 2014-00000394, Regional Health System, Venice, Italy; and the University of Padua Research Project (PRAT) CPDA133979. We thank patients and their families for participating in the study.
Publisher Copyright:
© 2018 Heart Rhythm Society
PY - 2019/5
Y1 - 2019/5
N2 - 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.
AB - 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.
KW - Arrhythmogenic cardiomyopathy
KW - Sudden cardiac death
KW - Targeted gene panel
KW - TP63 gene
KW - PPP1R13L gene
KW - RIGHT-VENTRICULAR CARDIOMYOPATHY
KW - P63 GENE
KW - MUTATIONS
KW - P53
KW - ADHESION
KW - IASPP
U2 - 10.1016/j.hrthm.2018.11.015
DO - 10.1016/j.hrthm.2018.11.015
M3 - Article
C2 - 30453078
SN - 1547-5271
VL - 16
SP - 773
EP - 780
JO - Heart Rhythm
JF - Heart Rhythm
IS - 5
ER -