What is the clinical evidence from this study?

Study design: Observational. Population: Spinal muscular atrophy (n=12747). Intervention: Genome sequencing-based SMN copy-number caller vs. Orthogonal methods (digital PCR, MLPA). Primary outcome: Agreement of SMN1 copy number calls with orthogonal methods.

February 18, 2020Genetics in Medicine149 citationsOpen Access

Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data

XCXiao Chen ASAlba Sanchis‐Juan CFCourtney E. French

Key Result

A novel genome sequencing-based SMN copy-number caller achieved 99.8% agreement for SMN1 and 99.7% for SMN2 compared to orthogonal methods, with 100% precision for both SMA and carriers.

Study Design

Type

Observational (n=12,747)

Multicenter

Yes

Structured PICO

Does a novel genome sequencing-based method accurately identify SMN1 and SMN2 copy numbers for SMA diagnosis and carrier screening?

Population

12,747 genomes from the 1000 Genomes Project and NIHR BioResource Project analyzed to determine SMN1 and SMN2 copy numbers for SMA carrier screening.

Intervention

A novel method to identify the copy number of SMN1 and SMN2 using genome sequencing data by analyzing read depth and eight informative reference genome differences

Comparator

Orthogonal methods

Outcome

Agreement of SMN1 and SMN2 copy number calls with orthogonal methods (recall and precision)surrogate

A novel genome sequencing-based method accurately identifies SMN1 and SMN2 copy numbers, enabling comprehensive SMA testing and carrier screening.

Limitations

Cannot quantify the exact role of deletions, duplications, or gene conversion driving copy number changes.
Detection of silent carriers relies on a SNP with variable risk association across populations.
Does not currently detect other pathogenic variants in SMN1 that account for approximately 5% of SMA cases.

Abstract

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.

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