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Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss
PURPOSE: Hearing loss (HL) is the most common sensory disorder in children. Prompt molecular diagnosis may guide screening and management, especially in syndromic cases when HL is the single presenting feature. Exome sequencing (ES) is an appealing diagnostic tool for HL as the genetic causes are hi...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group US
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295269/ https://www.ncbi.nlm.nih.gov/pubmed/29907799 http://dx.doi.org/10.1038/s41436-018-0004-x |
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author | Sheppard, Sarah Biswas, Sawona Li, Mindy H. Jayaraman, Vijayakumar Slack, Ian Romasko, Edward J. Sasson, Ariella Brunton, Joshua Rajagopalan, Ramakrishnan Sarmady, Mahdi Abrudan, Jenica L. Jairam, Sowmya DeChene, Elizabeth T. Ying, Xiahoan Choi, Jiwon Wilkens, Alisha Raible, Sarah E. Scarano, Maria I. Santani, Avni Pennington, Jeffrey W. Luo, Minjie Conlin, Laura K. Devkota, Batsal Dulik, Matthew C. Spinner, Nancy B. Krantz, Ian D. |
author_facet | Sheppard, Sarah Biswas, Sawona Li, Mindy H. Jayaraman, Vijayakumar Slack, Ian Romasko, Edward J. Sasson, Ariella Brunton, Joshua Rajagopalan, Ramakrishnan Sarmady, Mahdi Abrudan, Jenica L. Jairam, Sowmya DeChene, Elizabeth T. Ying, Xiahoan Choi, Jiwon Wilkens, Alisha Raible, Sarah E. Scarano, Maria I. Santani, Avni Pennington, Jeffrey W. Luo, Minjie Conlin, Laura K. Devkota, Batsal Dulik, Matthew C. Spinner, Nancy B. Krantz, Ian D. |
author_sort | Sheppard, Sarah |
collection | PubMed |
description | PURPOSE: Hearing loss (HL) is the most common sensory disorder in children. Prompt molecular diagnosis may guide screening and management, especially in syndromic cases when HL is the single presenting feature. Exome sequencing (ES) is an appealing diagnostic tool for HL as the genetic causes are highly heterogeneous. METHODS: ES was performed on a prospective cohort of 43 probands with HL. Sequence data were analyzed for primary and secondary findings. Capture and coverage analysis was performed for genes and variants associated with HL. RESULTS: The diagnostic rate using ES was 37.2%, compared with 15.8% for the clinical HL panel. Secondary findings were discovered in three patients. For 247 genes associated with HL, 94.7% of the exons were targeted for capture and 81.7% of these exons were covered at 20× or greater. Further analysis of 454 randomly selected HL-associated variants showed that 89% were targeted for capture and 75% were covered at a read depth of at least 20×. CONCLUSION: ES has an improved yield compared with clinical testing and may capture diagnoses not initially considered due to subtle clinical phenotypes. Technical challenges were identified, including inadequate capture and coverage of HL genes. Additional considerations of ES include secondary findings, cost, and turnaround time. |
format | Online Article Text |
id | pubmed-6295269 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-62952692018-12-15 Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss Sheppard, Sarah Biswas, Sawona Li, Mindy H. Jayaraman, Vijayakumar Slack, Ian Romasko, Edward J. Sasson, Ariella Brunton, Joshua Rajagopalan, Ramakrishnan Sarmady, Mahdi Abrudan, Jenica L. Jairam, Sowmya DeChene, Elizabeth T. Ying, Xiahoan Choi, Jiwon Wilkens, Alisha Raible, Sarah E. Scarano, Maria I. Santani, Avni Pennington, Jeffrey W. Luo, Minjie Conlin, Laura K. Devkota, Batsal Dulik, Matthew C. Spinner, Nancy B. Krantz, Ian D. Genet Med Article PURPOSE: Hearing loss (HL) is the most common sensory disorder in children. Prompt molecular diagnosis may guide screening and management, especially in syndromic cases when HL is the single presenting feature. Exome sequencing (ES) is an appealing diagnostic tool for HL as the genetic causes are highly heterogeneous. METHODS: ES was performed on a prospective cohort of 43 probands with HL. Sequence data were analyzed for primary and secondary findings. Capture and coverage analysis was performed for genes and variants associated with HL. RESULTS: The diagnostic rate using ES was 37.2%, compared with 15.8% for the clinical HL panel. Secondary findings were discovered in three patients. For 247 genes associated with HL, 94.7% of the exons were targeted for capture and 81.7% of these exons were covered at 20× or greater. Further analysis of 454 randomly selected HL-associated variants showed that 89% were targeted for capture and 75% were covered at a read depth of at least 20×. CONCLUSION: ES has an improved yield compared with clinical testing and may capture diagnoses not initially considered due to subtle clinical phenotypes. Technical challenges were identified, including inadequate capture and coverage of HL genes. Additional considerations of ES include secondary findings, cost, and turnaround time. Nature Publishing Group US 2018-06-15 2018 /pmc/articles/PMC6295269/ /pubmed/29907799 http://dx.doi.org/10.1038/s41436-018-0004-x Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. |
spellingShingle | Article Sheppard, Sarah Biswas, Sawona Li, Mindy H. Jayaraman, Vijayakumar Slack, Ian Romasko, Edward J. Sasson, Ariella Brunton, Joshua Rajagopalan, Ramakrishnan Sarmady, Mahdi Abrudan, Jenica L. Jairam, Sowmya DeChene, Elizabeth T. Ying, Xiahoan Choi, Jiwon Wilkens, Alisha Raible, Sarah E. Scarano, Maria I. Santani, Avni Pennington, Jeffrey W. Luo, Minjie Conlin, Laura K. Devkota, Batsal Dulik, Matthew C. Spinner, Nancy B. Krantz, Ian D. Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss |
title | Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss |
title_full | Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss |
title_fullStr | Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss |
title_full_unstemmed | Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss |
title_short | Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss |
title_sort | utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295269/ https://www.ncbi.nlm.nih.gov/pubmed/29907799 http://dx.doi.org/10.1038/s41436-018-0004-x |
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