Neurology. Genetics · 2026
Long-Read HiFi Genome Sequencing Resolves Retrotransposon-Mediated Deletions in TANGO2 Deficiency Disorder.
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Sabbagh Quentin, Villa Tobón Felipe, Kazemi Zahra, Lentini Laura, Dilenge Marie-Emmanuelle, Buhas Daniela, Pastinen Tomi, Thiffault Isabelle, Bernard Geneviève
Аннотация
BACKGROUND: 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).
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: 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).
DISCUSSION: 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.
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: 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).
DISCUSSION: 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.