Kalliopi Pilichou1, Elisabetta Lazzarini1, Ilaria Rigato1, Rudy Celeghin1, Marzia De Bortoli1, Marina Perazzolo Marra1, Marco Cason1, Jan Jongbloed1, Martina Calore1, Stefania Rizzo1, Daniela Regazzo1, Giulia Poloni1, Sabino Iliceto1, Luciano Daliento1, Pietro Delise1, Domenico Corrado1, J Peter Van Tintelen1, Gaetano Thiene1, Alessandra Rampazzo1, Cristina Basso1, Barbara Bauce2, Alessandra Lorenzon1, Gianluca Occhi1. 1. From the Departments of Cardiac, Thoracic, and Vascular Sciences (K.P., E.L., I.R., R.C., M.P.M., M.C., S.R., S.I., L.D., D.C., G. T., C.B., B.B.) and Medicine (D.R.), University of Padua, Italy; Department of Biology, University of Padua, Italy (M.D.B., M.C., G.P., A.R., A.L., G.O.); University Medical Center Groningen, University of Groningen, The Netherlands (J.J.); Cardiology Division, Casa di Cura Pederzoli, Peschiera del Garda, Italy (P.D.); and Department of Clinical Genetics, University of Amsterdam, The Netherlands (J.P.V.T.). 2. From the Departments of Cardiac, Thoracic, and Vascular Sciences (K.P., E.L., I.R., R.C., M.P.M., M.C., S.R., S.I., L.D., D.C., G. T., C.B., B.B.) and Medicine (D.R.), University of Padua, Italy; Department of Biology, University of Padua, Italy (M.D.B., M.C., G.P., A.R., A.L., G.O.); University Medical Center Groningen, University of Groningen, The Netherlands (J.J.); Cardiology Division, Casa di Cura Pederzoli, Peschiera del Garda, Italy (P.D.); and Department of Clinical Genetics, University of Amsterdam, The Netherlands (J.P.V.T.). barbara.bauce@unipd.it.
Abstract
BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is an inherited heart muscle disease associated with point mutations in genes encoding for cardiac desmosome proteins. Conventional mutation screening is positive in ≈50% of probands. Copy number variations (CNVs) have recently been linked to AC pointing to the need to determine the prevalence of CNVs in desmosomal genes and to evaluate disease penetrance by cosegregation analysis in family members. METHODS AND RESULTS: A total of 160 AC genotype-negative probands for 5 AC desmosomal genes by conventional mutation screening underwent multiplex ligation-dependent probe amplification. Nine heterozygous CNVs were identified in 11 (6.9%) of the 160 probands. Five carried a deletion of the entire plakophilin-2 (PKP2) gene, 2 a deletion of only PKP2 exon 4, 1 a deletion of the PKP2 exons 6 to 11, 1 a PKP2 duplication of 5' untranslated region till exon 1, 1 the desmocollin-2 (DSC2) duplication of exons 7 to 9, and 1 a large deletion of chromosome 18 comprising both DSC2 and desmoglein-2 genes. All probands were affected by moderate-severe forms of the disease, whereas 10 (32%) of the 31 family members carrying one of these deletions fulfilled the diagnostic criteria. CONCLUSIONS: Genomic rearrangements were detected in ≈7% of AC probands negative for pathogenic point mutations in desmosomal genes, highlighting the potential of CNVs analysis to substantially increase the diagnostic yield of genetic testing. Genotype-phenotype correlation demonstrated the presence of the disease in about one third of family members carrying the CNV, underlying the role of other factors in the development and progression of the disease.
BACKGROUND:Arrhythmogenic cardiomyopathy (AC) is an inherited heart muscle disease associated with point mutations in genes encoding for cardiac desmosome proteins. Conventional mutation screening is positive in ≈50% of probands. Copy number variations (CNVs) have recently been linked to AC pointing to the need to determine the prevalence of CNVs in desmosomal genes and to evaluate disease penetrance by cosegregation analysis in family members. METHODS AND RESULTS: A total of 160 AC genotype-negative probands for 5 AC desmosomal genes by conventional mutation screening underwent multiplex ligation-dependent probe amplification. Nine heterozygous CNVs were identified in 11 (6.9%) of the 160 probands. Five carried a deletion of the entire plakophilin-2 (PKP2) gene, 2 a deletion of only PKP2 exon 4, 1 a deletion of the PKP2 exons 6 to 11, 1 a PKP2 duplication of 5' untranslated region till exon 1, 1 the desmocollin-2 (DSC2) duplication of exons 7 to 9, and 1 a large deletion of chromosome 18 comprising both DSC2 and desmoglein-2 genes. All probands were affected by moderate-severe forms of the disease, whereas 10 (32%) of the 31 family members carrying one of these deletions fulfilled the diagnostic criteria. CONCLUSIONS: Genomic rearrangements were detected in ≈7% of AC probands negative for pathogenic point mutations in desmosomal genes, highlighting the potential of CNVs analysis to substantially increase the diagnostic yield of genetic testing. Genotype-phenotype correlation demonstrated the presence of the disease in about one third of family members carrying the CNV, underlying the role of other factors in the development and progression of the disease.
Authors: Robyn J Hylind; Alexandre C Pereira; Daniel Quiat; Stephanie F Chandler; Thomas M Roston; William T Pu; Vassilios J Bezzerides; Jonathan G Seidman; Christine E Seidman; Dominic J Abrams Journal: Circ Genom Precis Med Date: 2022-05-10
Authors: Barry M O'Callaghan; Jules C Hancox; Alan G Stuart; Catherine Armstrong; Maggie M Williams; Alison Hills; Hazel Pearce; Carolyn L Dent; Mary Gable; Mark A Walsh Journal: HeartRhythm Case Rep Date: 2018-08-04
Authors: Domenico Corrado; Peter J van Tintelen; William J McKenna; Richard N W Hauer; Aris Anastastakis; Angeliki Asimaki; Cristina Basso; Barbara Bauce; Corinna Brunckhorst; Chiara Bucciarelli-Ducci; Firat Duru; Perry Elliott; Robert M Hamilton; Kristina H Haugaa; Cynthia A James; Daniel Judge; Mark S Link; Francis E Marchlinski; Andrea Mazzanti; Luisa Mestroni; Antonis Pantazis; Antonio Pelliccia; Martina Perazzolo Marra; Kalliopi Pilichou; Pyotr G A Platonov; Alexandros Protonotarios; Alessandra Rampazzo; Jeffry E Saffitz; Ardan M Saguner; Christian Schmied; Sanjay Sharma; Hari Tandri; Anneline S J M Te Riele; Gaetano Thiene; Adalena Tsatsopoulou; Wojciech Zareba; Alessandro Zorzi; Thomas Wichter; Frank I Marcus; Hugh Calkins Journal: Eur Heart J Date: 2020-04-07 Impact factor: 29.983