Detection of 5q-Spinal Muscular Atrophy by Short- and Long-Read Sequencing

Background: Early diagnosis of 5q spinal muscular atrophy (5q-SMA) is critical to enable timely therapy. In addition to SMN1 gene deletions, SMN1 SNVs have come into focus. Due to the high homologies within the SMN1/SMN2 locus, sequence analysis to identify SNVs of the SMN1 gene using standard Sanger or short-read sequencing methods is unreliable. The objective was to establish comprehensive SMA testing that includes detection of SMN1/SMN2 SNVs and assignment to the SMN1 gene. Methods: A bioinformatics workflow to detect homozygous SMN1 deletions and SMN1 SNVs on short-read sequencing was applied, followed by a targeted long-read sequencing approach. Results: Fourteen patients were diagnosed with 5q-SMA based on (1) homozygous SMN1 deletion (nine patients), (2) SMN1 deletion and hemizygous SNV (three patients), and (3) compound heterozygous SNVs in SMN1 (two patients). Conclusion: Both short-read sequencing and long-read sequencing have their roles in diagnostic testing, and their combined use can significantly enhance the accuracy and comprehensiveness of genomic analysis in clinical settings. As technology continues to advance, the integration of these sequencing approaches may become more common, allowing for a more comprehensive understanding of genetic variations and their impact on human health. Publication History Article published online: 13 November 2023 © 2023. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany