Validation of a high resolution NGS method for detecting spinal muscular atrophy carriers among phase 3 participants in the 1000 Genomes Project. Issue 1 (December 2015)

• Record Type: Journal Article
• Authors: Larson, Jessica; Silver, Ari; Chan, Dalin; Borroto, Carlos; Spurrier, Brett; Silver, Lee
• Is Part Of: BMC medical genetics. Volume 16:Issue 1(2015)
• Page Start: 1
• Page End: 14
• Publication Date: 2015-12
• Subjects: 1000 Genomes Project -- Carrier testing -- DNA-seq -- Exome-seq -- Genetic testing -- Next-generation sequencing (NGS) -- SMN1 -- SMN2 -- Spinal muscular atrophy (SMA); Medical genetics -- Periodicals; 616.04205
• DOI: 10.1186/s12881-015-0246-2
• Languages: English
• ISSNs: 1471-2350

Abstract

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 ofSMN1 andSMN2 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 herSMN1 andSMN2 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.