%0 Journal Article %J Am J Hum Genet %D 2016 %T Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations. %A Lalani, Seema R %A Liu, Pengfei %A Rosenfeld, Jill A %A Watkin, Levi B %A Chiang, Theodore %A Leduc, Magalie S %A Zhu, Wenmiao %A Ding, Yan %A Pan, Shujuan %A Vetrini, Francesco %A Miyake, Christina Y %A Shinawi, Marwan %A Gambin, Tomasz %A Eldomery, Mohammad K %A Akdemir, Zeynep Hande Coban %A Emrick, Lisa %A Wilnai, Yael %A Schelley, Susan %A Koenig, Mary Kay %A Memon, Nada %A Farach, Laura S %A Coe, Bradley P %A Azamian, Mahshid %A Hernandez, Patricia %A Zapata, Gladys %A Jhangiani, Shalini N %A Donna M Muzny %A Lotze, Timothy %A Clark, Gary %A Wilfong, Angus %A Northrup, Hope %A Adesina, Adekunle %A Bacino, Carlos A %A Scaglia, Fernando %A Bonnen, Penelope E %A Crosson, Jane %A Duis, Jessica %A Maegawa, Gustavo H B %A Coman, David %A Inwood, Anita %A McGill, Jim %A Eric Boerwinkle %A Graham, Brett %A Beaudet, Art %A Eng, Christine M %A Hanchard, Neil A %A Xia, Fan %A Orange, Jordan S %A Richard A Gibbs %A Lupski, James R %A Yang, Yaping %K Alleles %K Arabs %K Arrhythmias, Cardiac %K Base Sequence %K Child %K Child, Preschool %K Endoplasmic Reticulum Stress %K Exome %K Exons %K Female %K Gene Deletion %K Golgi Apparatus %K Hispanic or Latino %K Homozygote %K Humans %K Infant %K Male %K Molecular Sequence Data %K Muscle Weakness %K Pedigree %K Rhabdomyolysis %K White People %X

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.

%B Am J Hum Genet %V 98 %P 347-57 %8 2016 Feb 04 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/26805781?dopt=Abstract %R 10.1016/j.ajhg.2015.12.008