domingo, 2 de diciembre de 2018

A targeted next-generation gene panel reveals a novel heterozygous nonsense variant in TP63 gene in Arrhythmogenic Cardiomyopathy patients. - PubMed - NCBI

2018 Nov 16. pii: S1547-5271(18)31160-3. doi: 10.1016/j.hrthm.2018.11.015. [Epub ahead of print]

A targeted next-generation gene panel reveals a novel heterozygous nonsense variant in TP63 gene in Arrhythmogenic Cardiomyopathy patients.

Poloni G1, Calore M1, Rigato I2, Marras E3, Minervini G4, Mazzotti E2, Lorenzon A1, Astrid Li Mura IE5, Telatin A5, Zara I5, Simionati B5, Marra MP2, Ponti J1, Occhi G1, Vitiello L6, Daliento L2, Thiene G2, Basso C2, Corrado D2, Tosatto S7, Bauce B2, Rampazzo A8, De Bortoli M1.

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Abstract

BACKGROUND:

Arrhythmogenic Cardiomyopathy (ACM) is associated with arrhythmias and risk of sudden death. Mutations in genes encoding proteins of cardiac intercalated discs account for about 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 ACM probands.

METHODS:

DNA samples from 40 ACM probands, 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 resulted to carry rare variant(s) predicted to be damaging; specifically, 9 (22.5%) showed one or more variants in genes associated with ACM and/or with other inherited heart diseases and 10 (25%) showed variants in candidate genes. Amongst the latter, we focused on two 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 iASPP are known to be interacting partners. iASPP 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 TP63 variant has been scored as likely pathogenic and the PPP1R13L variant as of uncertain significance. Importantly, the mutant TP63 allele leads to nonsense-mediated-mRNA decay, causing haploinsufficiency.