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

Journal: American Journal Of Human Genetics

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.

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