Emma S Singer1,2, Samantha B Ross1,2, Jon R Skinner3,4, Robert G Weintraub5,6, Jodie Ingles1,2,7, Christopher Semsarian1,2,7, Richard D Bagnall8,9. 1. Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, NSW, Australia. 2. Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. 3. Cardiac Inherited Disease Group New Zealand, Green Lane Paediatric and Congenital Cardiac Services, Starship Children's Hospital, Auckland, New Zealand. 4. Department of Paediatrics Child and Youth Health, The University of Auckland, Auckland, New Zealand. 5. Cardiology Department, Royal Children's Hospital, Melbourne, VIC, Australia. 6. Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia. 7. Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. 8. Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, NSW, Australia. r.bagnall@centenary.org.au. 9. Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. r.bagnall@centenary.org.au.
Abstract
PURPOSE: Copy-number variant (CNV) analysis is increasingly performed in genetic diagnostics. We leveraged recent gene curation efforts and technical standards for interpretation and reporting of CNVs to characterize clinically relevant CNVs in patients with inherited heart disease and sudden cardiac death. METHODS: Exome sequencing data were analyzed for CNVs using eXome-Hidden Markov Model tool in 48 established disease genes. CNV breakpoint junctions were characterized. CNVs were classified using the American College of Medical Genetics and Genomics technical standards. RESULTS: We identified eight CNVs in 690 unrelated probands (1.2%). Characterization of breakpoint junctions revealed nonhomologous end joining was responsible for four deletions, whereas one duplication was caused by nonallelic homologous recombination between duplicated sequences in MYH6 and MYH7. Identifying the precise breakpoint junctions determined the genomic involvement and proved useful for interpreting the clinical relevance of CNVs. Three large deletions involving TTN, MYBPC3, and KCNH2 were classified as pathogenic in three patients. Haplotype analysis of a deletion in ACTN2, found in two families, suggests the deletion was caused by an ancestral event. CONCLUSION: CNVs infrequently cause inherited heart diseases and should be investigated when standard genetic testing does not reveal a genetic diagnosis.
PURPOSE: Copy-number variant (CNV) analysis is increasingly performed in genetic diagnostics. We leveraged recent gene curation efforts and technical standards for interpretation and reporting of CNVs to characterize clinically relevant CNVs in patients with inherited heart disease and sudden cardiac death. METHODS: Exome sequencing data were analyzed for CNVs using eXome-Hidden Markov Model tool in 48 established disease genes. CNV breakpoint junctions were characterized. CNVs were classified using the American College of Medical Genetics and Genomics technical standards. RESULTS: We identified eight CNVs in 690 unrelated probands (1.2%). Characterization of breakpoint junctions revealed nonhomologous end joining was responsible for four deletions, whereas one duplication was caused by nonallelic homologous recombination between duplicated sequences in MYH6 and MYH7. Identifying the precise breakpoint junctions determined the genomic involvement and proved useful for interpreting the clinical relevance of CNVs. Three large deletions involving TTN, MYBPC3, and KCNH2 were classified as pathogenic in three patients. Haplotype analysis of a deletion in ACTN2, found in two families, suggests the deletion was caused by an ancestral event. CONCLUSION: CNVs infrequently cause inherited heart diseases and should be investigated when standard genetic testing does not reveal a genetic diagnosis.
Authors: Sana M Al-Khatib; William G Stevenson; Michael J Ackerman; William J Bryant; David J Callans; Anne B Curtis; Barbara J Deal; Timm Dickfeld; Michael E Field; Gregg C Fonarow; Anne M Gillis; Christopher B Granger; Stephen C Hammill; Mark A Hlatky; José A Joglar; G Neal Kay; Daniel D Matlock; Robert J Myerburg; Richard L Page Journal: Circulation Date: 2018-09-25 Impact factor: 29.690
Authors: Melissa Anfinson; Robert H Fitts; John W Lough; Jeanne M James; Pippa M Simpson; Stephanie S Handler; Michael E Mitchell; Aoy Tomita-Mitchell Journal: J Cardiovasc Dev Dis Date: 2022-05-03