Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations

Seema R. Lalani, Pengfei Liu, Jill A. Rosenfeld, Levi B. Watkin, Theodore Chiang, Magalie S. Leduc, Wenmiao Zhu, Yan Ding, Shujuan Pan, Francesco Vetrini, Christina Y. Miyake, Marwan Shinawi, Tomasz Gambin, Mohammad K. Eldomery, Zeynep Hande Coban Akdemir, Lisa Emrick, Yael Wilnai, Susan Schelley, Mary Kay Koenig, Nada MemonLaura S. Farach, Bradley P. Coe, Mahshid Azamian, Patricia Hernandez, Gladys Zapata, Shalini N. Jhangiani, Donna M. Muzny, Timothy Lotze, Gary Clark, Angus Wilfong, Hope Northrup, Adekunle Adesina, Carlos A. Bacino, Fernando Scaglia, Penelope E. Bonnen, Jane Crosson, Jessica Duis, Gustavo H.B. Maegawa, David Coman, Anita Inwood, Jim McGill, Eric Boerwinkle, Brett Graham, Art Beaudet, Christine M. Eng, Neil A. Hanchard, Fan Xia, Jordan S. Orange, Richard A. Gibbs, James R. Lupski, Yaping Yang

Research output: Contribution to journalArticlepeer-review

92 Scopus citations


The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous ∼34 kb deletion affecting exons 3-9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3-9. Additionally, a homozygous exons 4-6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3-9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations.

Original languageEnglish
Pages (from-to)347-357
Number of pages11
JournalAmerican journal of human genetics
Issue number2
StatePublished - Feb 4 2016


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