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Am J Hum Genet. 2016 Feb 4;98(2):347-57. doi: 10.1016/j.ajhg.2015.12.008. Epub 2016 Jan 21.

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

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: seemal@bcm.edu.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA.
3
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
4
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital Center for Human Immuno-Biology, Houston, TX 77030, USA.
5
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
6
Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA.
7
Department of Pediatric Cardiology, Texas Children's Hospital, Houston, TX 77030, USA.
8
Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
9
Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
10
Division of Medical Genetics, Stanford School of Medicine, Stanford, CA 94304, USA.
11
Division of Child & Adolescent Neurology, Department of Pediatrics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
12
Division of Cardiology, DCH Regional Medical Center, Tuscaloosa, AL 35401, USA.
13
Division of Medical Genetics, Department of Pediatrics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
14
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
15
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
16
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
17
Department of Pathology, Texas Children's Hospital, Houston, TX 77030, USA.
18
Division of Pediatric Cardiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
19
Mckusick-Nathans Inst. of Genetic Medicine & Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
20
Mckusick-Nathans Inst. of Genetic Medicine & Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pediatrics, Division of Genetics & Metabolism, University of Florida, Gainsville, FL 32610, USA.
21
Department of Metabolic Medicine, Lady Cilento Children's Hospital, South Brisbane, QLD 4101, Australia.
22
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Human Genetics Center, School of Public Health, University of Houston Health Science Center, Houston, TX 77030, USA.
23
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
24
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
25
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA. Electronic address: yapingy@bcm.edu.

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.

PMID:
26805781
PMCID:
PMC4746334
DOI:
10.1016/j.ajhg.2015.12.008
[Indexed for MEDLINE]
Free PMC Article

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