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

TANGO2 deficiency disorder (TDD) is a rare autosomal recessive condition characterized by neurodevelopmental delay, epilepsy, and metabolic crises, mainly caused by recurrent deletions in TANGO2. 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).

Long-read HiFi GS was performed on blood-derived genomic DNA from affected individuals in both families using the Revio system (Pacific Biosciences).

Homozygous deletions spanning exons 3-9 in family 1 and exons 4-6 in family 2 were identified. These recurrent deletions resulted from genomic recombination between an Alu 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).

This study highlights the diagnostic value of long-read HiFi GS for detecting structural variants (SVs) overlooked by standard-of-care NGS and enabling base-pair level breakpoint characterization. It provides the first evidence of retrotransposon-mediated recombination causing recurrent TANGO2 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.