%0 Journal Article %J Genet Med %D 2020 %T Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data. %A Chen, Xiao %A Sanchis-Juan, Alba %A French, Courtney E %A Connell, Andrew J %A Delon, Isabelle %A Kingsbury, Zoya %A Chawla, Aditi %A Halpern, Aaron L %A Taft, Ryan J %A Bentley, David R %A Butchbach, Matthew E R %A Raymond, F Lucy %A Eberle, Michael A %K Base Sequence %K Child %K Child, Preschool %K Humans %K Muscular Atrophy, Spinal %K Survival of Motor Neuron 1 Protein %X

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.

%B Genet Med %V 22 %P 945-953 %8 2020 05 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/32066871?dopt=Abstract %R 10.1038/s41436-020-0754-0