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

Area of Science:

• Genomics
• Molecular Biology
• Rare Diseases

Background:

• TANGO2 deficiency disorder (TDD) is a rare autosomal recessive condition.
• It is characterized by neurodevelopmental delay, epilepsy, and metabolic crises.
• Recurrent deletions in the TANGO2 gene are the primary cause of TDD.

Purpose of the Study:

• To identify the genetic cause of TDD in two unrelated families.
• To investigate the utility of long-read HiFi genome sequencing for detecting structural variants.
• To elucidate the mechanism underlying recurrent TANGO2 deletions.

Main Methods:

• Long-read HiFi genome sequencing (GS) was performed on affected individuals.
• The Revio system (Pacific Biosciences) was utilized for GS.
• Analysis focused on identifying structural variants, specifically deletions.

Main Results:

• Homozygous deletions in TANGO2 (exons 3-9 in family 1, exons 4-6 in family 2) were identified.
• These deletions resulted from retrotransposon-mediated recombination (ERV1 and L1MB8).
• The mechanism was consistent with fork stalling and template switching/microhomology-mediated break-induced repair (FoSTeS/MMBIR).

Conclusions:

• Long-read HiFi GS is valuable for detecting structural variants missed by conventional NGS.
• This study provides the first evidence of retrotransposon-mediated recombination causing recurrent TANGO2 deletions.
• TDD prevalence may be underestimated due to undetected structural variants.