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Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data

PURPOSE: Spinal muscular atrophy (SMA), caused by loss of the SMN1 gene, is a leading cause of early childhood death. Due to the near identical sequences of SMN1 and SMN2, analysis of this region is challenging. Population-wide SMA screening to quantify the SMN1 copy number (CN) is recommended by th...

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Autores principales: Chen, Xiao, Sanchis-Juan, Alba, French, Courtney E., Connell, Andrew J., Delon, Isabelle, Kingsbury, Zoya, Chawla, Aditi, Halpern, Aaron L., Taft, Ryan J., Bentley, David R., Butchbach, Matthew E. R., Raymond, F. Lucy, Eberle, Michael A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200598/
https://www.ncbi.nlm.nih.gov/pubmed/32066871
http://dx.doi.org/10.1038/s41436-020-0754-0
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author Chen, Xiao
Sanchis-Juan, Alba
French, Courtney E.
Connell, Andrew J.
Delon, Isabelle
Kingsbury, Zoya
Chawla, Aditi
Halpern, Aaron L.
Taft, Ryan J.
Bentley, David R.
Butchbach, Matthew E. R.
Raymond, F. Lucy
Eberle, Michael A.
author_facet Chen, Xiao
Sanchis-Juan, Alba
French, Courtney E.
Connell, Andrew J.
Delon, Isabelle
Kingsbury, Zoya
Chawla, Aditi
Halpern, Aaron L.
Taft, Ryan J.
Bentley, David R.
Butchbach, Matthew E. R.
Raymond, F. Lucy
Eberle, Michael A.
author_sort Chen, Xiao
collection PubMed
description PURPOSE: Spinal muscular atrophy (SMA), caused by loss of the SMN1 gene, is a leading cause of early childhood death. Due to the near identical sequences of SMN1 and SMN2, analysis of this region is challenging. Population-wide SMA screening to quantify the SMN1 copy number (CN) is recommended by the American College of Medical Genetics and Genomics. METHODS: We developed a method that accurately identifies the CN of SMN1 and SMN2 using genome sequencing (GS) data by analyzing read depth and eight informative reference genome differences between SMN1/2. RESULTS: We characterized SMN1/2 in 12,747 genomes, identified 1568 samples with SMN1 gains or losses and 6615 samples with SMN2 gains or losses, and calculated a pan-ethnic carrier frequency of 2%, consistent with previous studies. Additionally, 99.8% of our SMN1 and 99.7% of SMN2 CN calls agreed with orthogonal methods, with a recall of 100% for SMA and 97.8% for carriers, and a precision of 100% for both SMA and carriers. CONCLUSION: This SMN copy-number caller can be used to identify both carrier and affected status of SMA, enabling SMA testing to be offered as a comprehensive test in neonatal care and an accurate carrier screening tool in GS sequencing projects.
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spelling pubmed-72005982020-05-07 Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data Chen, Xiao Sanchis-Juan, Alba French, Courtney E. Connell, Andrew J. Delon, Isabelle Kingsbury, Zoya Chawla, Aditi Halpern, Aaron L. Taft, Ryan J. Bentley, David R. Butchbach, Matthew E. R. Raymond, F. Lucy Eberle, Michael A. Genet Med Article PURPOSE: Spinal muscular atrophy (SMA), caused by loss of the SMN1 gene, is a leading cause of early childhood death. Due to the near identical sequences of SMN1 and SMN2, analysis of this region is challenging. Population-wide SMA screening to quantify the SMN1 copy number (CN) is recommended by the American College of Medical Genetics and Genomics. METHODS: We developed a method that accurately identifies the CN of SMN1 and SMN2 using genome sequencing (GS) data by analyzing read depth and eight informative reference genome differences between SMN1/2. RESULTS: We characterized SMN1/2 in 12,747 genomes, identified 1568 samples with SMN1 gains or losses and 6615 samples with SMN2 gains or losses, and calculated a pan-ethnic carrier frequency of 2%, consistent with previous studies. Additionally, 99.8% of our SMN1 and 99.7% of SMN2 CN calls agreed with orthogonal methods, with a recall of 100% for SMA and 97.8% for carriers, and a precision of 100% for both SMA and carriers. CONCLUSION: This SMN copy-number caller can be used to identify both carrier and affected status of SMA, enabling SMA testing to be offered as a comprehensive test in neonatal care and an accurate carrier screening tool in GS sequencing projects. Nature Publishing Group US 2020-02-18 2020 /pmc/articles/PMC7200598/ /pubmed/32066871 http://dx.doi.org/10.1038/s41436-020-0754-0 Text en © The Author(s) 2020 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
Chen, Xiao
Sanchis-Juan, Alba
French, Courtney E.
Connell, Andrew J.
Delon, Isabelle
Kingsbury, Zoya
Chawla, Aditi
Halpern, Aaron L.
Taft, Ryan J.
Bentley, David R.
Butchbach, Matthew E. R.
Raymond, F. Lucy
Eberle, Michael A.
Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data
title Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data
title_full Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data
title_fullStr Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data
title_full_unstemmed Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data
title_short Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data
title_sort spinal muscular atrophy diagnosis and carrier screening from genome sequencing data
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200598/
https://www.ncbi.nlm.nih.gov/pubmed/32066871
http://dx.doi.org/10.1038/s41436-020-0754-0
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