Recurrent muscle weakness with rhabdomyolysis, metabolic crises, and cardiac arrhythmia due to bi-allelic TANGO2 mutations

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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
Coman, David
et al.
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2016
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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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American Journal of Human Genetics

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98

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2

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Biological sciences

Biomedical and clinical sciences

Science & Technology

Life Sciences & Biomedicine

Genetics & Heredity

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DEHYDROGENASE-DEFICIENCY

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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; Coman, D; et al., Recurrent muscle weakness with rhabdomyolysis, metabolic crises, and cardiac arrhythmia due to bi-allelic TANGO2 mutations, American Journal of Human Genetics, 2016, 98 (2), pp. 347-357

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