title: Exome sequencing reveals a homozygous mutation in TWINKLE as the cause of multisystemic failure including renal tubulopathy in three siblings.
abstract: 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.
authors: Department of Paediatrics, Children's Hospital, London Health Sciences Centre, Western University, London, ON, Canada. Chitra.Prasad@lhsc.on.ca
authors: Chitra
authors: C
authors: Prasad
authors: Serge B
authors: SB
authors: Melançon
authors: C Anthony
authors: CA
authors: Rupar
authors: Asuri N
authors: AN
authors: Prasad
authors: Laura Dempsey
authors: LD
authors: Nunez
authors: David S
authors: DS
authors: Rosenblatt
authors: Jacek
authors: J
authors: Majewski
mesh_terms: D003241:Consanguinity; D004265:DNA Helicases / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D059472:Exome; D017809:Fatal Outcome; D005260:Female; D006720:Homozygote; D006801:Humans; D007223:Infant; D007418:Intestinal Pseudo-Obstruction; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D017237:Mitochondrial Encephalomyopathies; D017240:Mitochondrial Myopathies / Q000235:genetics* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics*; D039141:Muscular Dystrophy, Oculopharyngeal; D009154:Mutation; D009886:Ophthalmoplegia / Q000151:congenital; D010641:Phenotype; D035781:Siblings; D028361:Mitochondrial Diseases
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D004265:DNA Helicases; C431576:TWNK protein, human