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BMC Medical Genetics
Published in: BMC Medical Genetics 1/2015

Open Access 01-12-2015 | Technical advance

Validation of a high resolution NGS method for detecting spinal muscular atrophy carriers among phase 3 participants in the 1000 Genomes Project

Authors: Jessica L. Larson, Ari J. Silver, Dalin Chan, Carlos Borroto, Brett Spurrier, Lee M. Silver

Published in: BMC Medical Genetics | Issue 1/2015

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Abstract

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.
Appendix
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Metadata
Title
Validation of a high resolution NGS method for detecting spinal muscular atrophy carriers among phase 3 participants in the 1000 Genomes Project
Authors
Jessica L. Larson
Ari J. Silver
Dalin Chan
Carlos Borroto
Brett Spurrier
Lee M. Silver
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2015
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/s12881-015-0246-2

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