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Systems-Level Integration of Multi-Omics Identifies Genetic Modifiers of TANGO2 Deficiency Disorder.

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TANGO2 deficiency disorder shows varied symptoms even in siblings with identical gene variants. Lipid metabolism and gene expression modifiers influence disease severity, impacting neurodevelopment and offering therapeutic insights.

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Area of Science:

  • Genetics and Systems Biology
  • Rare Disease Pathophysiology
  • Genotype-Phenotype Correlation

Background:

  • TANGO2 deficiency disorder is a rare autosomal recessive disease with significant phenotypic variability.
  • Identical TANGO2 variants can lead to vastly different clinical outcomes, even within families.
  • Understanding modifier mechanisms is crucial for explaining disease severity and guiding personalized treatments.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying phenotypic variability in TANGO2 deficiency disorder.
  • To identify genetic and expression-based modifiers influencing disease severity in affected individuals.
  • To apply an integrative systems biology framework for genotype-phenotype correlation in a rare disease.

Main Methods:

  • Developed an integrative systems biology framework combining exome sequencing, transcriptomics, and variant effect prediction.
  • Applied the framework to two siblings with identical TANGO2 variants but disparate clinical outcomes.
  • Utilized personalized protein-protein interaction networks and multi-omics analyses for high specificity.

Main Results:

  • The severely affected sibling showed a burden of common APOB variants and altered expression of VLDLR, NTN1, and LDHA, implicating lipid metabolism and neurodevelopmental pathways.
  • The asymptomatic sibling had a protective EP300 3'-UTR variant and no APOB variant burden, suggesting enhanced post-transcriptional regulation.
  • Identified disrupted lipid metabolism and neurodevelopmental pathways in the affected sibling, contrasting with regulatory mechanisms in the asymptomatic sibling.

Conclusions:

  • Lipid metabolism is a key pathway in TANGO2 deficiency pathophysiology.
  • Autophagy and mitophagy emerge as potential modifier mechanisms contributing to phenotypic variability.
  • The integrative multi-omics framework is valuable for rare disease research and personalized therapeutic strategies.