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

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. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Citation

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 Memon, Laura 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. Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations. American journal of human genetics. 2016 Feb 4;98(2):347-57

Mesh Tags

PMID: 26805781

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