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

Area of Science:

• Genomics
• Cytogenetics
• Human Genetics

Background:

• Revisiting a 20-year-old case of developmental delay and epilepsy.
• Initial cytogenetic analysis revealed a de novo terminal inverted-duplication at 8q24.3, with ambiguous interpretation due to limitations in detecting smaller rearrangements.

Purpose of the Study:

• To re-evaluate a previously reported case using advanced cytogenomic approaches.
• To precisely characterize the complex genomic rearrangement at 8q24.3 and investigate its potential link to the patient's phenotype.

Main Methods:

• Cytogenomics
• Karyotype and Fluorescence In Situ Hybridization (FISH) analysis
• Chromosomal Microarray (CMA)
• Optical Genome Mapping (OGM)
• Short-read Whole Genome Sequencing (srWGS)

Main Results:

• Identification of a complex genomic configuration at 8q24.3, including clustered duplications and inverted duplications (DUP-TRP/INV-DUP).
• Observed overexpression of genes within the amplified regions.
• Despite advanced analysis, a definitive genotype-phenotype correlation was not established.

Conclusions:

• Modern cytogenomic techniques can uncover complex rearrangements missed by older methods.
• The precise genomic architecture at 8q24.3 was elucidated, but its direct contribution to the patient's developmental delay and epilepsy remains uncertain.