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 & 31 others 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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)347-357
Number of pages11
JournalAmerican Journal of Human Genetics
Volume98
Issue number2
DOIs
StatePublished - Feb 4 2016

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Rhabdomyolysis
Muscle Weakness
Hispanic Americans
Cardiac Arrhythmias
Exons
Mutation
Homozygote
Exome
Hyperammonemia
Endoplasmic Reticulum Stress
Hypoglycemia
Tachycardia
Population
Drosophila
Fibroblasts
Alleles
Organizations
Databases
Morbidity

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

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

In: American Journal of Human Genetics, Vol. 98, No. 2, 04.02.2016, p. 347-357.

Research output: Contribution to journalArticle

Lalani, 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, ZHC, Emrick, L, Wilnai, Y, Schelley, S, Koenig, MK, 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 2016, 'Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations', American Journal of Human Genetics, vol. 98, no. 2, pp. 347-357. https://doi.org/10.1016/j.ajhg.2015.12.008
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. / Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations. In: American Journal of Human Genetics. 2016 ; Vol. 98, No. 2. pp. 347-357.
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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.",
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AU - Lalani, Seema R.

AU - Liu, Pengfei

AU - Rosenfeld, Jill A.

AU - Watkin, Levi B.

AU - Chiang, Theodore

AU - Leduc, Magalie S.

AU - Zhu, Wenmiao

AU - Ding, Yan

AU - Pan, Shujuan

AU - Vetrini, Francesco

AU - Miyake, Christina Y.

AU - Shinawi, Marwan

AU - Gambin, Tomasz

AU - Eldomery, Mohammad K.

AU - Akdemir, Zeynep Hande Coban

AU - Emrick, Lisa

AU - Wilnai, Yael

AU - Schelley, Susan

AU - Koenig, Mary Kay

AU - Memon, Nada

AU - Farach, Laura S.

AU - Coe, Bradley P.

AU - Azamian, Mahshid

AU - Hernandez, Patricia

AU - Zapata, Gladys

AU - Jhangiani, Shalini N.

AU - Muzny, Donna M.

AU - Lotze, Timothy

AU - Clark, Gary

AU - Wilfong, Angus

AU - Northrup, Hope

AU - Adesina, Adekunle

AU - Bacino, Carlos A.

AU - Scaglia, Fernando

AU - Bonnen, Penelope E.

AU - Crosson, Jane

AU - Duis, Jessica

AU - Maegawa, Gustavo H B

AU - Coman, David

AU - Inwood, Anita

AU - McGill, Jim

AU - Boerwinkle, Eric

AU - Graham, Brett

AU - Beaudet, Art

AU - Eng, Christine M.

AU - Hanchard, Neil A.

AU - Xia, Fan

AU - Orange, Jordan S.

AU - Gibbs, Richard A.

AU - Lupski, James R.

AU - Yang, Yaping

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