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De novo deletions and duplications of 17q25.3 cause susceptibility to cardiovascular malformations
BACKGROUND: Genomic disorders resulting from deletion or duplication of genomic segments are known to be an important cause of cardiovascular malformations (CVMs). In our previous study, we identified a unique individual with a de novo 17q25.3 deletion from a study of 714 individuals with CVM. METHO...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472615/ https://www.ncbi.nlm.nih.gov/pubmed/26070612 http://dx.doi.org/10.1186/s13023-015-0291-0 |
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author | Probst, F. J. James, R. A. Burrage, L. C. Rosenfeld, J. A. Bohan, T. P. Melver, C. H. Ward Magoulas, P. Austin, E. Franklin, A. I. A. Azamian, M. Xia, F. Patel, A. Bi, W. Bacino, C. Belmont, J.W. Ware, S. M. Shaw, C. Cheung, S.W. Lalani, S. R. |
author_facet | Probst, F. J. James, R. A. Burrage, L. C. Rosenfeld, J. A. Bohan, T. P. Melver, C. H. Ward Magoulas, P. Austin, E. Franklin, A. I. A. Azamian, M. Xia, F. Patel, A. Bi, W. Bacino, C. Belmont, J.W. Ware, S. M. Shaw, C. Cheung, S.W. Lalani, S. R. |
author_sort | Probst, F. J. |
collection | PubMed |
description | BACKGROUND: Genomic disorders resulting from deletion or duplication of genomic segments are known to be an important cause of cardiovascular malformations (CVMs). In our previous study, we identified a unique individual with a de novo 17q25.3 deletion from a study of 714 individuals with CVM. METHODS: To understand the contribution of this locus to cardiac malformations, we reviewed the data on 60,000 samples submitted for array comparative genomic hybridization (CGH) studies to Medical Genetics Laboratories at Baylor College of Medicine, and ascertained seven individuals with segmental aneusomy of 17q25. We validated our findings by studying another individual with a de novo submicroscopic deletion of this region from Cytogenetics Laboratory at Cincinnati Children’s Hospital. Using bioinformatic analyses including protein-protein interaction network, human tissue expression patterns, haploinsufficiency scores, and other annotation systems, including a training set of 251 genes known to be linked to human cardiac disease, we constructed a pathogenicity score for cardiac phenotype for each of the 57 genes within the terminal 2.0 Mb of 17q25.3. RESULTS: We found relatively high penetrance of cardiovascular defects (~60 %) with five deletions and three duplications, observed in eight unrelated individuals. Distinct cardiac phenotypes were present in four of these subjects with non-recurrent de novo deletions (range 0.08 Mb–1.4 Mb) in the subtelomeric region of 17q25.3. These included coarctation of the aorta (CoA), total anomalous pulmonary venous return (TAPVR), ventricular septal defect (VSD) and atrial septal defect (ASD). Amongst the three individuals with variable size duplications of this region, one had patent ductus arteriosus (PDA) at 8 months of age. CONCLUSION: The distinct cardiac lesions observed in the affected patients and the bioinformatics analyses suggest that multiple genes may be plausible drivers of the cardiac phenotype within this gene-rich critical interval of 17q25.3. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-015-0291-0) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4472615 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-44726152015-06-20 De novo deletions and duplications of 17q25.3 cause susceptibility to cardiovascular malformations Probst, F. J. James, R. A. Burrage, L. C. Rosenfeld, J. A. Bohan, T. P. Melver, C. H. Ward Magoulas, P. Austin, E. Franklin, A. I. A. Azamian, M. Xia, F. Patel, A. Bi, W. Bacino, C. Belmont, J.W. Ware, S. M. Shaw, C. Cheung, S.W. Lalani, S. R. Orphanet J Rare Dis Research BACKGROUND: Genomic disorders resulting from deletion or duplication of genomic segments are known to be an important cause of cardiovascular malformations (CVMs). In our previous study, we identified a unique individual with a de novo 17q25.3 deletion from a study of 714 individuals with CVM. METHODS: To understand the contribution of this locus to cardiac malformations, we reviewed the data on 60,000 samples submitted for array comparative genomic hybridization (CGH) studies to Medical Genetics Laboratories at Baylor College of Medicine, and ascertained seven individuals with segmental aneusomy of 17q25. We validated our findings by studying another individual with a de novo submicroscopic deletion of this region from Cytogenetics Laboratory at Cincinnati Children’s Hospital. Using bioinformatic analyses including protein-protein interaction network, human tissue expression patterns, haploinsufficiency scores, and other annotation systems, including a training set of 251 genes known to be linked to human cardiac disease, we constructed a pathogenicity score for cardiac phenotype for each of the 57 genes within the terminal 2.0 Mb of 17q25.3. RESULTS: We found relatively high penetrance of cardiovascular defects (~60 %) with five deletions and three duplications, observed in eight unrelated individuals. Distinct cardiac phenotypes were present in four of these subjects with non-recurrent de novo deletions (range 0.08 Mb–1.4 Mb) in the subtelomeric region of 17q25.3. These included coarctation of the aorta (CoA), total anomalous pulmonary venous return (TAPVR), ventricular septal defect (VSD) and atrial septal defect (ASD). Amongst the three individuals with variable size duplications of this region, one had patent ductus arteriosus (PDA) at 8 months of age. CONCLUSION: The distinct cardiac lesions observed in the affected patients and the bioinformatics analyses suggest that multiple genes may be plausible drivers of the cardiac phenotype within this gene-rich critical interval of 17q25.3. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-015-0291-0) contains supplementary material, which is available to authorized users. BioMed Central 2015-06-14 /pmc/articles/PMC4472615/ /pubmed/26070612 http://dx.doi.org/10.1186/s13023-015-0291-0 Text en © Probst et al. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Probst, F. J. James, R. A. Burrage, L. C. Rosenfeld, J. A. Bohan, T. P. Melver, C. H. Ward Magoulas, P. Austin, E. Franklin, A. I. A. Azamian, M. Xia, F. Patel, A. Bi, W. Bacino, C. Belmont, J.W. Ware, S. M. Shaw, C. Cheung, S.W. Lalani, S. R. De novo deletions and duplications of 17q25.3 cause susceptibility to cardiovascular malformations |
title | De novo deletions and duplications of 17q25.3 cause susceptibility to cardiovascular malformations |
title_full | De novo deletions and duplications of 17q25.3 cause susceptibility to cardiovascular malformations |
title_fullStr | De novo deletions and duplications of 17q25.3 cause susceptibility to cardiovascular malformations |
title_full_unstemmed | De novo deletions and duplications of 17q25.3 cause susceptibility to cardiovascular malformations |
title_short | De novo deletions and duplications of 17q25.3 cause susceptibility to cardiovascular malformations |
title_sort | de novo deletions and duplications of 17q25.3 cause susceptibility to cardiovascular malformations |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472615/ https://www.ncbi.nlm.nih.gov/pubmed/26070612 http://dx.doi.org/10.1186/s13023-015-0291-0 |
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