A founder variant in TANGO2 p.(Leu148Trp) in ten Palestinian families: clinical characterization and haplotype analysis of TANGO2 deficiency disorder.

backgroundTANGO2 deficiency disorder (TDD) is a rare autosomal recessive condition characterized by recurrent metabolic crises, rhabdomyolysis, encephalopathy, seizures, intellectual disability, and life-threatening cardiac arrhythmias.

methodsHere, we describe 16 affected individuals from 10 consanguineous Palestinian families harboring a shared homozygous missense variant in TANGO2 (NM_152906.7:c.443T > G; NP_690870.3:p.(Leu148Trp)). Exome sequencing identified the variant in three probands and targeted Sanger sequencing confirmed segregation in all remaining families. The variant is absent from population databases and is predicted to be deleterious by multiple in silico tools. Microsatellite marker analysis was performed using five short tandem repeat (STR) markers spanning the TANGO2 locus.

resultsClinical presentation was heterogeneous, including developmental delay, recurrent encephalopathy, rhabdomyolysis, seizures, and cardiac involvement. Microsatellite marker analysis revealed a conserved ancestral haplotype flanking the TANGO2 locus in all genotyped affected individuals, supporting a founder effect in this population. Supportive management including coenzyme Q10 and B-complex vitamins (B-100) was commonly used; consistent with prior reports, some families described reduced frequency and/or severity of spells following supplementation.

conclusionsThese findings provide strong clinical, genetic, and haplotype evidence supporting reclassification of the TANGO2 p.(Leu148Trp) variant as likely pathogenic and highlight the importance of early molecular diagnosis and targeted screening strategies in high-consanguinity populations.