Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data.

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Sanchis-Juan, Alba 
French, Courtney E 
Connell, Andrew J 
Delon, Isabelle 

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.

bioinformatics, carrier screening, copy-number analysis, genome sequencing (GS), spinal muscular atrophy (SMA), Base Sequence, Child, Child, Preschool, Humans, Muscular Atrophy, Spinal, Survival of Motor Neuron 1 Protein
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Genet Med
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Elsevier BV
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)