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

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

Abstract

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.
Author Seema R. Lalani
Seema R. Lalani ,,
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, Pengfei Liu
Pengfei Liu,,
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, Jill A. Rosenfeld
Jill A. Rosenfeld,,
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, Levi B. Watkin
Levi B. Watkin ,,
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, Theodore Chiang
Theodore Chiang,,
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, Magalie S. Leduc
Magalie S. Leduc,,
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, Wenmiao Zhu
Wenmiao Zhu ,,
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, Yan Ding
Yan Ding,,
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, Shujuan Pan
Shujuan Pan,,
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, Francesco Vetrini
Francesco Vetrini ,,
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et al.`
Journal seriesAmerican Journal of Human Genetics, ISSN 0002-9297
Issue year2016
Vol98
No2
Pages347-357
Publication size in sheets0.5
DOIDOI:10.1016/j.ajhg.2015.12.008
URL http://www.sciencedirect.com/science/article/pii/S0002929715005030
Languageen angielski
Score (nominal)45
ScoreMinisterial score = 45.0, 27-03-2017, ArticleFromJournal
Ministerial score (2013-2016) = 45.0, 27-03-2017, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 9.025 (2) - 2016=10.362 (5)
Citation count*21 (2018-06-20)
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