Felipe Villa Tobón

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.

Leukodystrophies (LDs) are a group of rare, genetic disorders unified by their hallmark involvement of the cerebral white matter. They are typically characterized as progressive disorders, resulting in severe neurologic decline and premature death within months to years after onset. Managing LDs therefore requires lifelong, multidisciplinary care, a challenge compounded by their rarity and phenotypic heterogeneity, for which detailed clinical and scientific information is sometimes lacking. Research networks have proven useful in the rare disease community to unite efforts, increase awareness, and accelerate progress toward understanding and treating these often understudied conditions. Therefore, we established the Canadian Association for Research Excellence in Leukodystrophy (CARELeuko), a national network dedicated to improving LD care, research, and treatment within Canada. To better understand and address the most pressing needs for LDs in Canada, we engaged a diverse group of stakeholders including researchers, clinicians, and patient advocates to highlight and prioritize gaps in LD care and research. In this review, we discuss the key gaps identified in the Canadian LD landscape and outline strategies to address these challenges. This effort will inform the development of targeted initiatives aimed at improving outcomes for Canadian families affected by these debilitating disorders.