Long-read sequencing for rare human genetic diseases

J Hum Genet. 2020 Jan;65(1):11-19. doi: 10.1038/s10038-019-0671-8. Epub 2019 Sep 27.


During the past decade, the search for pathogenic mutations in rare human genetic diseases has involved huge efforts to sequence coding regions, or the entire genome, using massively parallel short-read sequencers. However, the approximate current diagnostic rate is <50% using these approaches, and there remain many rare genetic diseases with unknown cause. There may be many reasons for this, but one plausible explanation is that the responsible mutations are in regions of the genome that are difficult to sequence using conventional technologies (e.g., tandem-repeat expansion or complex chromosomal structural aberrations). Despite the drawbacks of high cost and a shortage of standard analytical methods, several studies have analyzed pathogenic changes in the genome using long-read sequencers. The results of these studies provide hope that further application of long-read sequencers to identify the causative mutations in unsolved genetic diseases may expand our understanding of the human genome and diseases. Such approaches may also be applied to molecular diagnosis and therapeutic strategies for patients with genetic diseases in the future.

Publication types

  • Review

MeSH terms

  • Chromosome Aberrations
  • DNA Transposable Elements / genetics
  • Genome, Human
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Rare Diseases / diagnosis
  • Rare Diseases / genetics*
  • Sequence Analysis, DNA / methods*
  • Sequence Deletion / genetics
  • Sequence Inversion / genetics
  • Tandem Repeat Sequences / genetics


  • DNA Transposable Elements