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 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.


CONCLUSIONS
Our process is a convenient, robust alternative to qPCR, which can easily be integrated into the analysis of large multi-gene NGS carrier screens.
GenePeeks, Inc., Cambridge, MA, USA. jlarson@genepeeks.com.
Jessica L
JL
Larson
GenePeeks, Inc., Cambridge, MA, USA. asilver@geneepeeks.com.|GenePeeks, Inc., New York, NY, USA. asilver@geneepeeks.com.
Ari J
AJ
Silver
GenePeeks, Inc., Cambridge, MA, USA. dalinchan@genepeeks.com.
Dalin
D
Chan
GenePeeks, Inc., New York, NY, USA. carlosborroto@genepeeks.com.
Carlos
C
Borroto
GenePeeks, Inc., New York, NY, USA. brettspurrier@genepeeks.com.
Brett
B
Spurrier
GenePeeks, Inc., Cambridge, MA, USA. lsilver@genepeeks.com.|GenePeeks, Inc., New York, NY, USA. lsilver@genepeeks.com.|Department of Molecular Biology and the Woodrow Wilson School of Public and International Affairs, Princeton University, Princeton, NJ, USA. lsilver@genepeeks.com.
Lee M
LM
Silver
D016022:Case-Control Studies; D015331:Cohort Studies; D006580:Genetic Carrier Screening / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D016045:Human Genome Project; D006801:Humans; D008957:Models, Genetic; D060885:Multiplex Polymerase Chain Reaction; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein