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

TitleRecurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations.
Publication TypeJournal Article
Year of Publication2016
AuthorsLalani, SR, Liu, P, Rosenfeld, JA, Watkin, LB, Chiang, T, Leduc, MS, Zhu, W, Ding, Y, Pan, S, Vetrini, F, Miyake, CY, Shinawi, M, Gambin, T, Eldomery, MK, Akdemir, ZHande Coba, Emrick, L, Wilnai, Y, Schelley, S, Koenig, MKay, Memon, N, Farach, LS, Coe, BP, Azamian, M, Hernandez, P, Zapata, G, Jhangiani, SN, Muzny, DM, Lotze, T, Clark, G, Wilfong, A, Northrup, H, Adesina, A, Bacino, CA, Scaglia, F, Bonnen, PE, Crosson, J, Duis, J, Maegawa, GHB, Coman, D, Inwood, A, McGill, J, Boerwinkle, E, Graham, B, Beaudet, A, Eng, CM, Hanchard, NA, Xia, F, Orange, JS, Gibbs, RA, Lupski, JR, Yang, Y
JournalAm J Hum Genet
Date Published2016 Feb 4
KeywordsAlleles, Arabs, Arrhythmias, Cardiac, Base Sequence, Child, Child, Preschool, Endoplasmic Reticulum Stress, European Continental Ancestry Group, Exome, Exons, Female, Gene Deletion, Golgi Apparatus, Hispanic Americans, Homozygote, Humans, Infant, Male, Molecular Sequence Data, Muscle Weakness, Pedigree, Rhabdomyolysis

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.

Alternate JournalAm. J. Hum. Genet.
PubMed ID26805781
PubMed Central IDPMC4746334
Grant ListR01 NS083726 / NS / NINDS NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
UL1 TR000371 / TR / NCATS NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States