Constitutional copy number amplifications: rare or under-evaluated? Revisiting a 25-year-old cold case

Eur J Hum Genet. 2025 Sep;33(9):1212-1216. doi: 10.1038/s41431-025-01883-0. Epub 2025 Jun 4.

Abstract

We reanalyzed through a cytogenomics approach a case published 20 years ago, describing a girl with developmental delay and epilepsy. Karyotype and FISH analysis showed a de novo 2.3 Mb terminal inverted-duplication at 8q24.3. The interpretation was inconsistent with the absence of a more distal deletion as expected for distal inverted duplications, and it was inconceivable to highlight rearrangements smaller than 5-10 Mb at that time. Chromosomal microarray (CMA), optical genome mapping (OGM), and short-read whole genome sequencing (srWGS) identified a complex configuration at 8q24.3, which resembles events like chromoanasynthesis or DUP-TRP/INV-DUP (duplication-triplication/inverted-duplication), both characterized by clustered duplications and triplications, some of which are inverted. In the EBV-line genes located in the amplified regions were overexpressed. Despite a more precise definition of the imbalance, we were unable to provide a clear-cut explanation for the proband's clinical features.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • DNA Copy Number Variations*
  • Developmental Disabilities* / diagnosis
  • Developmental Disabilities* / genetics
  • Epilepsy* / diagnosis
  • Epilepsy* / genetics
  • Female
  • Humans