Long-Read HiFi Genome Sequencing Resolves Retrotransposon-Mediated Deletions in TANGO2 Deficiency Disorder

Background: . This study reports the identification of TDD in 2 unrelated families using long-read HiFi genome sequencing (GS), which uncovered homozygous deletions missed by conventional next-generation sequencing (NGS). Methods: Long-read HiFi GS was performed on blood-derived genomic DNA from affected individuals in both families using the Revio system (Pacific Biosciences). Results: element and distinct retrotransposon subclasses: ERV1 in family 1 and L1MB8 in family 2. The lack of extended homology at breakpoint junctions, deletion sizes, and the dense repetitive genomic architecture support a replication-based rearrangement mechanism, most consistent with fork stalling and template switching or microhomology-mediated break-induced repair (FoSTeS/MMBIR). Discussion: deletions, elucidating the mechanistic underpinnings of genomic instability at this locus. Finally, these results suggest that TDD prevalence may be underestimated because of undetected SVs.