Intrachromosomal insertion as a diagnostic challenge: a hidden structural rearrangement causing recurrent duplication...

Area of Science:

• Genetics
• Reproductive Biology
• Genomic Medicine

Background:

• Intrachromosomal insertions are rare structural rearrangements often missed by conventional G-banding.
• Misinterpretation or failure to detect these insertions can lead to recurrent segmental imbalances in offspring.
• Accurate characterization is vital for predicting reproductive outcomes.

Purpose of the Study:

• To characterize an unresolved structural rearrangement in a family.
• To clarify the reproductive implications of intrachromosomal insertions.
• To investigate recurrent segmental imbalances in offspring.

Main Methods:

• Cytogenetic and molecular studies including G-banding.
• Preimplantation genetic testing for structural rearrangements (PGT-SR) using shallow whole-genome sequencing.
• Fluorescence in situ hybridization (FISH) and nanopore long-read sequencing for precise structural characterization.

Main Results:

• PGT-SR revealed recurrent segmental imbalances (4 duplications, 1 deletion) in 13 embryos.
• FISH and long-read sequencing identified the paternal rearrangement as an intrachromosomal inverted insertion: ins(9)(q34.13q22.33q21.31).
• The phenotypically normal father transmitted unbalanced gametes due to recombination, causing recurrent chromosomal abnormalities.

Conclusions:

• Balanced intrachromosomal insertions can cause recurrent duplications or deletions in offspring.
• Comprehensive analysis using FISH and long-read sequencing is essential for accurate diagnosis.
• Informed genetic counseling and reproductive decision-making rely on precise characterization of these rearrangements.