Novel homozygous stop-gain pathogenic variant of PPP1R13L gene leads to arrhythmogenic cardiomyopathy.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is a heritable cardiac disease with two main features: electric instability and myocardial fibro-fatty replacement. There is no defined treatment except for preventing arrhythmias and sudden death. Detecting causative mutations helps identify the disease pathogenesis and family members at risk. We used whole-exome sequencing to determine a genetic explanation for an ACM-positive patient from a consanguineous family. METHODS: After clinical analysis, cardiac magnetic resonance, and pathology, WES was performed on a two-year-old ACM proband. Variant confirmation and segregation of available pedigree members were performed by PCR and Sanger sequencing. The PPP1R13L gene was also analyzed for possible causative variants and their hitherto reported conditions. RESULTS: We found a novel homozygous stop-gain pathogenic variant, c.580C > T: p.Gln194Ter, in the PPP1R13L gene, which was confirmed and segregated by PCR and Sanger sequencing. This variant was not reported in any databases. CONCLUSIONS: WES is valuable for the identification of novel candidate genes. To our knowledge, this research is the first report of the PPP1R13L c.580C > T variant. The PPP1R13L variant was associated with ACM as confirmed by cardiac magnetic resonance and pathology. Our findings indicate that PPP1R13L should be included in ACM genetic testing to improve the identification of at-risk family members and the diagnostic yield.

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

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.