Long-Read DNA and RNA Sequencing to Streamline Clinical Genetic Testing and Reduce Barriers to Comprehensive Genetic Testing

J Appl Lab Med. 2024 Jan 3;9(1):138-150. doi: 10.1093/jalm/jfad107.


Background: Obtaining a precise molecular diagnosis through clinical genetic testing provides information about disease prognosis or progression, allows accurate counseling about recurrence risk, and empowers individuals to benefit from precision therapies or take part in N-of-1 trials. Unfortunately, more than half of individuals with a suspected Mendelian condition remain undiagnosed after a comprehensive clinical evaluation, and the results of any individual clinical genetic test ordered during a typical evaluation may take weeks or months to return. Furthermore, commonly used technologies, such as short-read sequencing, are limited in the types of disease-causing variation they can identify. New technologies, such as long-read sequencing (LRS), are poised to solve these problems.

Content: Recent technical advances have improved accuracy, increased throughput, and decreased the costs of commercially available LRS technologies. This has resolved many historical concerns about the use of LRS in the clinical environment and opened the door to widespread clinical adoption of LRS. Here, we review LRS technology, how it has been used in the research setting to clarify complex variants or identify disease-causing variation missed by prior clinical testing, and how it may be used clinically in the near future.

Summary: LRS is unique in that, as a single data source, it has the potential to replace nearly every other clinical genetic test offered today. When analyzed in a stepwise fashion, LRS will simplify laboratory processes, reduce barriers to comprehensive genetic testing, increase the rate of genetic diagnoses, and shorten the amount of time required to make a molecular diagnosis.

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Genetic Testing*
  • High-Throughput Nucleotide Sequencing* / methods
  • Humans
  • Prognosis
  • Sequence Analysis, DNA / methods
  • Sequence Analysis, RNA