Complex genomic rearrangements: an underestimated cause of rare diseases

Trends Genet. 2022 Nov;38(11):1134-1146. doi: 10.1016/j.tig.2022.06.003. Epub 2022 Jul 9.

Abstract

Complex genomic rearrangements (CGRs) are known contributors to disease but are often missed during routine genetic screening. Identifying CGRs requires (i) identifying copy number variants (CNVs) concurrently with inversions, (ii) phasing multiple breakpoint junctions incis, as well as (iii) detecting and resolving structural variants (SVs) within repeats. We demonstrate how combining cytogenetics and new sequencing methodologies is being successfully applied to gain insights into the genomic architecture of CGRs. In addition, we review CGR patterns and molecular features revealed by studying constitutional genomic disorders. These data offer invaluable lessons to individuals interested in investigating CGRs, evaluating their clinical relevance and frequency, as well as assessing their impact(s) on rare genetic diseases.

Keywords: chromosomal abnormalities; clinical diagnostics; constitutional diseases; genomic disorders; structural variation; whole-genome sequencing.

Publication types

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

MeSH terms

  • DNA Copy Number Variations / genetics
  • Gene Rearrangement / genetics
  • Genome, Human* / genetics
  • Genomics / methods
  • Humans
  • Rare Diseases* / genetics