1 - Serviço de Genética Médica, Área de Pediatria, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
2 - CGPP - Centro de Genética Preditiva e Preventiva, IBMC - Instituto de Biologia Molecular e Celular, I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
3 - Serviço de Genética, Departamento de Pediatria, Hospital de Santa Maria, Centro Hospitalar e Universitário Lisboa Norte, Lisboa, Portugal
4 - Serviço de Cardiologia Pediátrica, Hospital Santa Marta, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
5 - Serviço de Neuropediatria, Área de Pediatria, Hospital Dona Estefânia, Centro de Referência de Doenças Hereditárias do Metabolismo, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
6 - Unidade de Doenças Metabólicas, Área de Pediatria, Hospital Dona Estefânia, Centro de Referência de Doenças Hereditárias do Metabolismo, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
- Reunião nacional - 18.º Simpósio Internacional da Sociedade Portuguesa de Doenças Metabólicas (SPDM), sob a forma de poster
Background: Transport and Golgi organization 2 homolog (TANGO2) deficiency is an autosomal recessive disorder caused by bi-allelic variants in TANGO2 gene, located at 22q11.2 region. It is characterized by recurrent rhabdomyolysis, lactic acidosis, encephalopathy, and life‑threatening tachyarrhythmias, with developmental delay / intellectual disability.
Methods: Case studies.
Results: Case 1: A girl was first referred at 3y for severe global developmental delay, facial dysmorphisms, microcephaly, and spastic paraparesis. Previous extensive investigations including metabolic analysis, microarray and several single-gene molecular studies were normal. At 13yo she presented with severe rhabdomyolysis and complex ventricular tachycardia, requiring cardioversion. Trio-exome sequencing identified a homozygous splice-site variant in TANGO2:(NM_001322141.1) c.(728+1G>A), establishing the diagnosis of TANGO2 deficiency.
Case 2: A second girl was referred at 30m for micrognathia and palate cleft. The diagnosis of 22q11.2 microdeletion syndrome was suspected, and confirmed by FISH. Clinical evolution with recurrent episodes of muscle weakness and a rhabdomyolysis crisis at 16 yo prompted a re-evaluation of molecular diagnosis. A first approach with NGS-based multigene panel for neurological disorders was normal. Microarray study indicated a 22q11.2 microdeletion encompassing the TANGO2 gene. NGS reanalysis identified a hemizygous intragenic deletion in TANGO2:(NM_001322141.1) c.(179+1_180-1)_(*2502_?)del, thus confirming the diagnosis of TANGO2 disorder.
Conclusion: TANGO2-related disorder should be suspected in children with trigger-induced crises or arrhythmias and in 22q11.2 deletion syndrome, if encompassing the TANGO2 gene. Patient management should include avoidance of triggers and prompt treatment during crisis, as well as regular cardiology and neurology evaluation. Familial members benefit from genetic counselling, including discussion of reproductive options and pre‑symptomatic testing for at-risk children.
Palavras Chave: TANGO2-related disorder