Fork Stalling and Template Switching in a Complex der(6)dn with Duplication of 6q24.3qter and 6p25.3: A Case Report.

Abstract

Introduction: Partial trisomy of the 6q24qter region is a rare chromosomal disorder characterized by variable clinical features and poorly understood mechanistic origins.

Case presentation: We describe a de novo complex der(6) chromosome in a patient with features consistent with partial 6q trisomy syndrome, including congenital heart disease, growth restriction, developmental delay, and dysmorphic traits. Molecular Findings. Whole-genome sequencing (WGS) identified duplications of 1.5 Mb on 6p25.3 and 23.3 Mb on 6q24.3-qter. While the 6p duplication appears benign, the phenotype is likely driven by dosage-sensitive 6q genes (ARID1B, TAB2, QKI) and possible additive effects from other duplicated genes. No parental pericentric inversion was detected by classical or molecular cytogenetics, and WGS revealed no inversion-associated breakpoints. Instead, chimeric (q-/q+) and truncated reads at the 6q junction support a replication-based origin, such as reversed template switching. FISH confirmed direct insertion of the 6q segment into 6p25.3, without a del/dup pattern typical of inversion-derived recombinants. Notably, WGS detected no direct 6p-6q junction reads, but identified chimeric 6p-15q-6q reads with 2-bp microhomologies, suggesting that chromosome 15 transiently mediated the rearrangement. Interspersed telomeric sequences and flanking Alu elements were also found at both breakpoints.

Conclusion: Altogether, these findings support a model in which replication fork stalling and template switching-potentially facilitated by telomere dynamics and repetitive elements-led to the formation of a recombinant-like der(6) chromosome. This case highlights the mechanistic complexity of structural rearrangements and the role of replication-based errors in shaping human genomic variation.