Exome sequencing reveals a homozygous mutation in TWINKLE as the cause of multisystemic failure including renal tubulopathy in three siblings

Mol Genet Metab. 2013 Mar;108(3):190-4. doi: 10.1016/j.ymgme.2012.12.007. Epub 2012 Dec 31.


Three deceased infants from a Pakistani consanguineous family presented with a similar phenotype of cholestatic liver disease, hypotonia, severe failure to thrive, recurrent vomiting, renal tubulopathy, and a progressive neurodegenerative course. Mitochondrial DNA depletion syndrome was considered in view of multisystem involvement. Exome sequencing, revealed a homozygous novel mutation c.1183T>C (p.F395L) in exon 1 of the C10orf2 TWINKLE gene. The hepatocerebral phenotype is well recognized in association with recessive mutations involving the C10orf2 TWINKLE gene. The feature of renal tubulopathy adds to the multisystemic presentation in our patients and further demonstrates an expansion of the phenotype in mitochondrial DNA depletion syndrome associated with TWINKLE gene mutations. The absence of features of an epileptic encephalopathy appears to be of added interest.

Publication types

  • Case Reports

MeSH terms

  • Consanguinity
  • DNA Helicases / genetics*
  • DNA, Mitochondrial / genetics*
  • Exome*
  • Fatal Outcome
  • Female
  • Homozygote
  • Humans
  • Infant
  • Intestinal Pseudo-Obstruction
  • Kidney / metabolism
  • Kidney / pathology
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mitochondrial Encephalomyopathies
  • Mitochondrial Myopathies / genetics*
  • Mitochondrial Myopathies / pathology
  • Mitochondrial Proteins / genetics*
  • Muscular Dystrophy, Oculopharyngeal
  • Mutation*
  • Ophthalmoplegia / congenital
  • Phenotype
  • Siblings


  • DNA, Mitochondrial
  • Mitochondrial Proteins
  • DNA Helicases
  • TWNK protein, human

Supplementary concepts

  • Visceral myopathy familial external ophthalmoplegia