Document Type

Article

Publication Date

6-2026

Identifier

DOI: 10.1212/NXG.0000000000200377; PMCID: PMC13128312

Abstract

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

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.

Journal Title

Neurol Genet

Volume

12

Issue

3

First Page

200377

Last Page

200377

PubMed ID

42063611

Comments

This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Publisher's Link: https://doi.org/10.1212/nxg.0000000000200377

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