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|Title||Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data.|
|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||Chen, X, Sanchis-Juan, A, French, CE, Connell, AJ, Delon, I, Kingsbury, Z, Chawla, A, Halpern, AL, Taft, RJ, Bentley, DR, Butchbach, MER, F Raymond, L, Eberle, MA|
|Corporate Authors||NIHR BioResource|
|Date Published||2020 05|
|Keywords||Base Sequence, Child, Child, Preschool, Humans, Muscular Atrophy, Spinal, Survival of Motor Neuron 1 Protein|
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.
|Alternate Journal||Genet Med|
|PubMed Central ID||PMC7200598|
|Grant List||P20 GM103446 / GM / NIGMS NIH HHS / United States |
P30 GM114736 / GM / NIGMS NIH HHS / United States
UM1 HG008901 / HG / NHGRI NIH HHS / United States
RG65966 / DH / Department of Health / United Kingdom