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Validation of a high resolution NGS method for detecting spinal muscular atrophy carriers among phase 3 participants in the 1000 Genomes Project
BACKGROUND: Spinal muscular atrophy (SMA) is the most common pan-ethnic cause of early childhood death due to mutations in a single gene, SMN1. Most chromosome 5 homologs have a functional gene and dysfunctional copy, SMN2, with a single synonymous base substitution that results in faulty RNA splici...
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/PMC4625734/ https://www.ncbi.nlm.nih.gov/pubmed/26510457 http://dx.doi.org/10.1186/s12881-015-0246-2 |
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author | Larson, Jessica L. Silver, Ari J. Chan, Dalin Borroto, Carlos Spurrier, Brett Silver, Lee M. |
author_facet | Larson, Jessica L. Silver, Ari J. Chan, Dalin Borroto, Carlos Spurrier, Brett Silver, Lee M. |
author_sort | Larson, Jessica L. |
collection | PubMed |
description | BACKGROUND: Spinal muscular atrophy (SMA) is the most common pan-ethnic cause of early childhood death due to mutations in a single gene, SMN1. Most chromosome 5 homologs have a functional gene and dysfunctional copy, SMN2, with a single synonymous base substitution that results in faulty RNA splicing. However, the copy number of SMN1 and SMN2 is highly variable, and one in 60 adults worldwide are SMA carriers. Although population-wide screening is recommended, current SMA carrier tests have not been incorporated into targeted gene panels. METHODS: Here we describe a novel computational protocol for determining SMA carrier status based solely on individual exome data. Our method utilizes a Bayesian hierarchical model to quantify an individual’s carrier probability given only his or her SMN1 and SMN2 reads at six loci of interest. RESULTS: We find complete concordance with results obtained with the current qPCR-based testing standard in known SMA carriers and affecteds. We applied our protocol to the phase 3 cohort of the 1,000 Genomes Project and found carrier frequencies in multiple populations consistent with the present literature. CONCLUSION: Our process is a convenient, robust alternative to qPCR, which can easily be integrated into the analysis of large multi-gene NGS carrier screens. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12881-015-0246-2) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4625734 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-46257342015-10-30 Validation of a high resolution NGS method for detecting spinal muscular atrophy carriers among phase 3 participants in the 1000 Genomes Project Larson, Jessica L. Silver, Ari J. Chan, Dalin Borroto, Carlos Spurrier, Brett Silver, Lee M. BMC Med Genet Technical Advance BACKGROUND: Spinal muscular atrophy (SMA) is the most common pan-ethnic cause of early childhood death due to mutations in a single gene, SMN1. Most chromosome 5 homologs have a functional gene and dysfunctional copy, SMN2, with a single synonymous base substitution that results in faulty RNA splicing. However, the copy number of SMN1 and SMN2 is highly variable, and one in 60 adults worldwide are SMA carriers. Although population-wide screening is recommended, current SMA carrier tests have not been incorporated into targeted gene panels. METHODS: Here we describe a novel computational protocol for determining SMA carrier status based solely on individual exome data. Our method utilizes a Bayesian hierarchical model to quantify an individual’s carrier probability given only his or her SMN1 and SMN2 reads at six loci of interest. RESULTS: We find complete concordance with results obtained with the current qPCR-based testing standard in known SMA carriers and affecteds. We applied our protocol to the phase 3 cohort of the 1,000 Genomes Project and found carrier frequencies in multiple populations consistent with the present literature. CONCLUSION: Our process is a convenient, robust alternative to qPCR, which can easily be integrated into the analysis of large multi-gene NGS carrier screens. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12881-015-0246-2) contains supplementary material, which is available to authorized users. BioMed Central 2015-10-29 /pmc/articles/PMC4625734/ /pubmed/26510457 http://dx.doi.org/10.1186/s12881-015-0246-2 Text en © Larson et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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 | Technical Advance Larson, Jessica L. Silver, Ari J. Chan, Dalin Borroto, Carlos Spurrier, Brett Silver, Lee M. Validation of a high resolution NGS method for detecting spinal muscular atrophy carriers among phase 3 participants in the 1000 Genomes Project |
title | Validation of a high resolution NGS method for detecting spinal muscular atrophy carriers among phase 3 participants in the 1000 Genomes Project |
title_full | Validation of a high resolution NGS method for detecting spinal muscular atrophy carriers among phase 3 participants in the 1000 Genomes Project |
title_fullStr | Validation of a high resolution NGS method for detecting spinal muscular atrophy carriers among phase 3 participants in the 1000 Genomes Project |
title_full_unstemmed | Validation of a high resolution NGS method for detecting spinal muscular atrophy carriers among phase 3 participants in the 1000 Genomes Project |
title_short | Validation of a high resolution NGS method for detecting spinal muscular atrophy carriers among phase 3 participants in the 1000 Genomes Project |
title_sort | validation of a high resolution ngs method for detecting spinal muscular atrophy carriers among phase 3 participants in the 1000 genomes project |
topic | Technical Advance |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625734/ https://www.ncbi.nlm.nih.gov/pubmed/26510457 http://dx.doi.org/10.1186/s12881-015-0246-2 |
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