Using Long-Read Sequencing Techniques to Overcome Limitations of Routine Genetic Testing: Unraveling the Complexity of the SMN Locus

Abstract

The field of genetic sequencing is rapidly expanding, with significant consequences for research and clinical practice. Next-generation sequencing (NGS) technology allows for accurate, fast, and cost-effective genome sequencing. NGS is suitable to detect small-scale DNA alterations but not for substantial structural variations (SVs) and tandem repeats (TRs). As a result, NGS methods rely on additional tests to analyze such complex regions. Long-read sequencing (LRS) technology is developed in response to the limitations of NGS technologies and is capable of sequencing complex genomic regions without requiring additional tests. Spinal muscular atrophy (SMA) is a neuromuscular disease caused by defects in the survival motor neuron (SMN) locus. NGS has been used to analyze the SMN locus for decades. However, the relationship between genetic alterations within SMN locus and SMA phenotype variety is still not completely understood. LRS has been used to resolve complex regions and has identified a wide range of clinically relevant structural variants. This literature review shows that LRS could also be similarly used to analyze SMN locus. Furthermore, LRS could potentially identify genomic alterations that contribute to SMA phenotype variability and could be used as a genetic screening method to detect SMA silent carriers. Overall, the use of LRS in clinical studies could improve SMA diagnosis as well as be used in genetic counseling of individuals with a high risk of having a child with SMA.