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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Arabs / genetics
  • Arrhythmias, Cardiac / diagnosis
  • Arrhythmias, Cardiac / genetics*
  • Base Sequence
  • Child
  • Child, Preschool
  • Endoplasmic Reticulum Stress / genetics
  • European Continental Ancestry Group / genetics
  • Exome
  • Exons
  • Female
  • Gene Deletion
  • Golgi Apparatus / genetics
  • Golgi Apparatus / metabolism
  • Hispanic Americans / genetics
  • Homozygote
  • Humans
  • Infant
  • Male
  • Molecular Sequence Data
  • Muscle Weakness / diagnosis
  • Muscle Weakness / genetics*
  • Pedigree
  • Rhabdomyolysis / diagnosis
  • Rhabdomyolysis / genetics*