Breakpoint junction analysis for complex genomic rearrangements with the caldera volcano-like pattern

Area of Science:

• Genetics
• Genomics
• Molecular Biology

Background:

• Chromosomal triplications are classified into recurrent and nonrecurrent types.
• Nonrecurrent triplications often occur within duplicated segments, with duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) being a known mechanism.
• The TRP-DUP-TRP pattern is a rare chromosomal aberration observed in patients with neurodevelopmental disabilities.

Observation:

• The TRP-DUP-TRP pattern presents a unique "caldera volcano-like" signature in array-based comparative genomic hybridization (aCGH) analysis.
• This specific pattern was identified in two patients diagnosed with neurodevelopmental disabilities.
• Whole-genome sequencing, custom array analysis, and Sanger sequencing were employed to investigate the breakpoint junctions.

Findings:

• The TRP-DUP-TRP pattern was found to comprise two distinct breakpoint junction patterns in the studied patients.
• Patient 1 exhibited microhomologies at the breakpoint junctions.
• Patient 2 displayed more complex genomic architectures, including insertional segments.

Implications:

• Replication-based mechanisms are proposed as the underlying cause for the TRP-DUP-TRP chromosomal aberration pattern.
• Understanding these mechanisms is crucial for diagnosing and potentially managing rare genetic disorders.
• This research contributes to the broader understanding of structural variations and their role in human disease.