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

• Published in: American journal of human genetics Vol. 98; no. 2; pp. 347 - 357
• Main Authors: Lalani, Seema R., Liu, Pengfei, Rosenfeld, Jill A., Watkin, Levi B., Chiang, Theodore, Leduc, Magalie S., Zhu, Wenmiao, Ding, Yan, Pan, Shujuan, Vetrini, Francesco, Miyake, Christina Y., Shinawi, Marwan, Gambin, Tomasz, Eldomery, Mohammad K., Akdemir, Zeynep Hande Coban, Emrick, Lisa, Wilnai, Yael, Schelley, Susan, Koenig, Mary Kay, Memon, Nada, Farach, Laura S., Coe, Bradley P., Azamian, Mahshid, Hernandez, Patricia, Zapata, Gladys, Jhangiani, Shalini N., Muzny, Donna M., Lotze, Timothy, Clark, Gary, Wilfong, Angus, Northrup, Hope, Adesina, Adekunle, Bacino, Carlos A., Scaglia, Fernando, Bonnen, Penelope E., Crosson, Jane, Duis, Jessica, Maegawa, Gustavo H.B., Coman, David, Inwood, Anita, McGill, Jim, Boerwinkle, Eric, Graham, Brett, Beaudet, Art, Eng, Christine M., Hanchard, Neil A., Xia, Fan, Orange, Jordan S., Gibbs, Richard A., Lupski, James R., Yang, Yaping
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.02.2016; Cell Press; Elsevier
• Subjects: Alleles; Arabs - genetics; Arrhythmias, Cardiac - diagnosis; Arrhythmias, Cardiac - genetics; Base Sequence; Child; Child, Preschool; Endoplasmic Reticulum Stress - genetics; Exome; Exons; Female; Gene Deletion; Genetics; Golgi Apparatus - genetics; Golgi Apparatus - metabolism; Hispanic or Latino - genetics; Homozygote; Humans; Infant; Male; Molecular Sequence Data; Muscle Weakness - diagnosis; Muscle Weakness - genetics; Muscular system; Musculoskeletal diseases; Mutation; Pedigree; Rhabdomyolysis - diagnosis; Rhabdomyolysis - genetics; White People - genetics
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2015.12.008

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.