Clinical, genetic, and bioinformatics analysis of a novel TANGO2 mutation (c.263G > A) in an Iranian Azeri Turkish child with lethal metabolic encephalopathy

Abstract

TANGO2-related disorder exhibits significant genotypic and phenotypic heterogeneity, and the clinical significance of novel variants often requires confirmation through detailed case reporting. This case report describes a female child born to consanguineous parents with an unremarkable prenatal and perinatal history. Initial development was normal, but by the second year of life, she exhibited developmental regression, and seizures, which were controlled with levetiracetam. At age 5, she presented with acute encephalopathy, dark urine, rhabdomyolysis, hypoglycemia, and hyperammonemia following a febrile illness. Whole-exome sequencing (WES) identified a novel homozygous TANGO2 variant (c.263G > A, p.Arg88Gln), confirmed via Sanger sequencing, with both parents being heterozygous carriers. Bioinformatics analysis predicted pathogenic effects, including potential exon skipping and protein structural alterations. The variant was absent in 430 ethnically matched controls and major population databases (gnomAD, 1000 Genomes), supporting its pathogenicity. Despite management, the patient experienced recurrent metabolic crises and ultimately succumbed to severe rhabdomyolysis and renal failure at age 8. This case underscores the severe phenotypic consequences of biallelic TANGO2 mutations, including developmental delay, metabolic instability, and early mortality, while highlighting the importance of genetic diagnosis in unexplained pediatric encephalopathies.