| domain | strongest finding/statistic | evidence type/sample | source year and DOI/URL | confidence/limitation |
|---|---|---|---|---|
| Identifiers / genetics | TANGO2 deficiency disorder is an autosomal recessive disease caused by biallelic TANGO2 variants; disease mapping available as MONDO_0018820, and phenotype MIM/OMIM 616878 is cited in the literature; common recurrent alleles include the exon 3-9 deletion and c.460G>A (p.Gly154Arg) in some Hispanic/Latino families | Disease database + human clinical genetics; multiple cohorts | 2024 Open Targets disease-target association; 2022 Scientific Reports doi:10.1038/s41598-022-07076-9; 2019 JIMD doi:10.1002/jimd.12156; https://platform.opentargets.org (pqac-00000000, pqac-00000001, pqac-00000010) | High confidence for gene-disease validity and AR inheritance; variant-frequency details remain cohort-dependent and not population-screened globally |
| 20-patient phenotype cohort | In 20 patients from 14 families, neurodevelopmental delay occurred in 85% (17/20), acute metabolic crises in 85% (17/20), hypothyroidism in 60% (12/20); among crises: rhabdomyolysis 88% (15/17), neurologic symptoms 82% (14/17), cardiac features 71% (12/17) | Human multicenter cohort, n=20 | 2020/2021 J Inherit Metab Dis doi:10.1002/jimd.12314 https://doi.org/10.1002/jimd.12314 (pqac-00000011, pqac-00000009) | High confidence for broad phenotype spectrum; modest sample size and referral-center ascertainment bias |
| 27-patient cardiac crisis series | In 27 patients across 43 crisis admissions, QTc prolongation occurred in 100% with median QTc 547 ms; ventricular tachycardia in 78%, cardiomyopathy in 70%, cardiac arrest in 74%, mortality 37% (10 deaths; 6 arrhythmia-related) | Human retrospective multicenter cardiac crisis study, n=27 patients / 43 admissions | 2022 Heart Rhythm doi:10.1016/j.hrthm.2022.05.009 https://doi.org/10.1016/j.hrthm.2022.05.009 (pqac-00000005) | High confidence for severity during crises; estimates apply to severe admissions rather than all diagnosed patients |
| 2024 22q11.2 screening implementation | In 435 patients with 22q11.2 deletion syndrome, 21 met symptom-based criteria for TANGO2 testing, 9 underwent sequencing, and 0 were diagnosed with TDD; authors highlight underdiagnosis risk because TANGO2 lies within the deleted interval | Human retrospective multicenter screening study, n=435 | 2024 Am J Med Genet A doi:10.1002/ajmg.a.63778 https://doi.org/10.1002/ajmg.a.63778 (pqac-00000002) | Moderate confidence; useful implementation evidence, but negative yield may reflect incomplete testing and retrospective design |
| Lipid / acyl-CoA mechanism | TANGO2-deficient cells showed increased lysophosphatidic acid and decreased phosphatidic acid, enlarged lipid droplets, elevated ROS, and nutrient-sensitive worsening; authors propose impaired acyl-CoA availability for LPA-to-PA acylation | Experimental cell biology and lipidomics in HepG2 cells and patient fibroblasts | 2023 eLife doi:10.7554/eLife.85345 https://doi.org/10.7554/eLife.85345 (pqac-00000025) | Moderate-high confidence for lipid-homeostasis mechanism; exact primary molecular function of TANGO2 remains unsettled |
| Zebrafish model | tango2 loss caused growth defects, early lethality, smaller myofibers, and increased skeletal-muscle susceptibility to extrinsic stressors; 96% mortality by 3 months was reported in the model summary | Model organism study, zebrafish mutants | 2023 Dis Model Mech doi:10.1242/dmm.050092 https://doi.org/10.1242/dmm.050092 (pqac-00000023, pqac-00000024) | Moderate confidence; strong for stress-sensitive muscle phenotype, but fish may not capture full human neurocardiac disease |
| Vitamin B5 rescue | Pantothenic acid (vitamin B5) rescued multiple TANGO2-associated defects in Drosophila and restored trafficking defects in human cells; in flies, starvation survival improved to ~25 h at 50% survival versus ~12 h untreated, and heat-induced seizures were reduced by ~95% | Drosophila + human cell rescue experiments | 2023 J Inherit Metab Dis doi:10.1002/jimd.12579 https://doi.org/10.1002/jimd.12579 (pqac-00000015, pqac-00000020) | Moderate confidence preclinically; no randomized human efficacy trial yet |
| Vitamin B9 iPSC-cardiomyocyte rescue | High-dose folate virtually abolished arrhythmias in patient-derived iPSC-cardiomyocytes; rescue was blocked by methotrexate, supporting an intracellular folate-dependent mechanism | Human iPSC-cardiomyocyte disease model + supportive natural-history observation | 2024 JCI Insight doi:10.1172/jci.insight.171005 https://doi.org/10.1172/jci.insight.171005 (pqac-00000016) | Moderate confidence for mechanistic antiarrhythmic potential; clinical benefit in patients remains observational, not trial-proven |
| Current study infrastructure | NCT05374616 is a recruiting observational natural-history/biorepository study with planned enrollment of 300 and estimated completion in 2030; primary outcome tracks metabolic and cardiac crises over 10 years | ClinicalTrials.gov observational registry/biorepository | ClinicalTrials.gov NCT05374616 https://clinicaltrials.gov/study/NCT05374616 (pqac-00000030, pqac-00000008) | High confidence for real-world implementation status; non-interventional and not a treatment-efficacy study |


*Table: This table summarizes the strongest available evidence across clinical, mechanistic, therapeutic, and implementation domains for TANGO2 deficiency disorder. It highlights where the evidence is strongest and where major limitations remain.*