Abstract 19270: Large Genomic Rearrangements of Desmosomal Genes in Arrhythmogenic Cardiomyopathy
Introduction: Arrhythmogenic Cardiomyopathy (AC) is an inherited heart muscle disease associated with point mutations in genes encoding mainly components of the cardiac desmosome.
Hypothesis: Since conventional mutation screening fails to uncover approximately 50% of AC genetic variants, we aimed to assess the prevalence of copy number variants (CNVs) involving desmosomal genes in a large cohort of unrelated genotype negative AC index cases and evaluated the pathogenic role of these CNVs by family co-segregation.
Methods: 160 AC genotype negative probands for 5 AC-associated genes underwent Multiplex Ligation-dependent Probe Amplification (MLPA) and sequencing on a ABI 3500 (Thermoscientific). MLPA detected CNVs were further confirmed by quantitative Real-Time polymerase chain reaction on a Light Cycler 480 (Roche) and additional point mutations were excluded in other AC-related genes by targeted re-sequencing on a MiSeq platform (Illumina).
Results: CNVs analysis revealed 4 different plakophilin-2 (PKP2) and 2 cardiac-cadherins (desmocollin-2, DSC2; desmoglein-2,DSG2) gene rearrangements in 11 AC index cases (7%). An heterozygous deletion of the entire PKP2 gene (122kb) was found in five probands, PKP2 exon 4 in two, and PKP2 exons 6 to 11, an heterozygous duplication of PKP2 exon 1, a large 18q deletion comprising both DSC2 and DSG2 genes and a duplication of DSC2 exons 7-8, one each. All probands fulfilled AC definite diagnostic criteria with severe forms of the disease. Cascade genetic screening identified 27 of the 63 family members carrying one of these CNVs; five of them (19%) fulfilled the diagnostic criteria with a severe form of the disease, four had a borderline diagnosis and the remaining 18 had no clinical diagnostic criteria, except for the family history.
Conclusions: Genomic rearrangements are identified in 7% of AC probands negative for pathogenic point mutations in desmosomal genes. Our data highlight a role for CNVs analysis to increase the diagnostic yield of AC genetic testing. Preliminary genotype-phenotype correlation in family members shows a relatively low disease penetrance of CNVs, so that their role in the AC phenotype needs further evaluation.
Author Disclosures: K. Pilichou: None. E. Lazzarini: None. I. Rigato: None. R. Celeghin: None. M. Cason: None. M. De Bortoli: None. A. Rampazzo: None. P. van Tintelen: None. L. Daliento: None. P. Delise: None. D. Corrado: None. G. Thiene: None. C. Basso: None. B. Bauce: None. A. Lorenzon: None. G. Occhi: None.
- © 2016 by American Heart Association, Inc.