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Abstract Details

Genotype and symptom prevalence in TANGO2 disease: In-frame pathogenic variants affecting the proximal amino region of the TANGO2 protein correlate with a mitochondrial phenotype
Child Neurology and Developmental Neurology
Child Neurology and Developmental Neurology Posters (7:00 AM-5:00 PM)
039
To characterize the relative incidence of known pathogenic variants in TANGO2 disease and their correlation with reported phenotypes.
TANGO2 disease is an autosomal recessive, phenotypically heterogeneous, and frequently lethal childhood neurological disorder thought to arise from dual pathophysiological processes involving ER-Golgi trafficking and mitochondrial metabolism. These pathways, when perturbed independently, could theoretically result in disparate symptomatic presentations (e.g., isolated rhabdomyolysis versus seizures and developmental regression). Scrutiny of pauci-symptomatic phenotypes and in-frame variants in TANGO2 may help identify organelle-specific functional domains in the TANGO2 protein.
Genotype and phenotype data were extracted from patients with known TANGO2 disease by way of combined retrospective chart review (N=5), literature review (N=71), and analysis of the ClinVar database (2 additional pathogenic variants). Variants were mapped to the MANE reference sequence for the predominant TANGO2 isoform using the ENSEMBL genome browser.
Common neurological symptoms of TANGO2 disease (N=76) include developmental delay (92%) and regression (71%), rhabdomyolysis (78%), spasticity (78%), seizures (57%), and episodic ataxia (50%). A majority of children also experience metabolic crisis (83%) and cardiac arrhythmias (63%). Of the 29 reported pathogenic variants, deletion of exons 3-9 was the most commonly reported (38% of alleles; 44 homozygous, 15 heterozygous) and was observed in 28 separate families. All children with missense variants and in-frame deletions affecting the first 40 amino acids of the TANGO2 protein experienced developmental delay/regression and metabolic crisis, suggesting mitochondrial dysfunction. No clear genotype-phenotype correlations supportive of an isolated ER-Golgi phenotype could be established.
These findings corroborate recent cell-level observations demonstrating the critical role of a mitochondrial targeting sequence proximal to the amino terminus of TANGO2. Defects in ER-Golgi trafficking may arise secondary to a common mitochondrial pathway. The high prevalence of multi-exon deletions in patients with TANGO2 disease indicate the potential utility of a gene replacement approach to treatment.
Authors/Disclosures
Samuel J. Mackenzie, MD, PhD (Nationwide Children's Hospital)
PRESENTER 		Dr. Mackenzie has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Phlow, Corp. Dr. Mackenzie has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Everyday Health, Inc. Dr. Mackenzie has received intellectual property interests from a discovery or technology relating to health care.