title: Exome sequencing identifies complex I NDUFV2 mutations as a novel cause of Leigh syndrome.
abstract: BACKGROUND
  Two siblings with hypertrophic cardiomyopathy and brain atrophy were diagnosed with Complex I deficiency based on low enzyme activity in muscle and high lactate/pyruvate ratio in fibroblasts.
  
  
  METHODS
  Whole exome sequencing results of fibroblast gDNA from one sibling was narrowed down to 190 SNPs or In/Dels in 185 candidate genes by selecting non-synonymous coding sequence base pair changes that were not present in the SNP database.
  
  
  RESULTS
  Two compound heterozygous mutations were identified in both siblings in NDUFV2, encoding the 24 kDa subunit of Complex I. The intronic mutation (c.IVS2 + 1delGTAA) is disease causing and has been reported before. The other mutation is novel (c.669_670insG, p.Ser224Valfs*3) and predicted to cause a pathogenic frameshift in the protein. Subsequent investigation of 10 probands with complex I deficiency from different families revealed homozygosity for the intronic c.IVS2 + 1delGTAA mutation in a second, consanguineous family. In this family three of five siblings were affected. Interestingly, they presented with Leigh syndrome but no cardiac involvement. The same genotype had been reported previously in a two families but presenting with hypertrophic cardiomyopathy, trunk hypotonia and encephalopathy.
  
  
  CONCLUSIONS
  We have identified NDUFV2 mutations in two families with Complex I deficiency, including a novel mutation. The diagnosis of Leigh syndrome expands the clinical phenotypes associated with the c.IVS2 + 1delGTAA mutation in this gene.
authors.affiliation: Genetics & Genome Biology Program, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Toronto, ON M5G 0A4, Canada. Electronic address: jessie.cameron@sickkids.ca.
authors.forename: Jessie M
authors.initials: JM
authors.lastname: Cameron
authors.affiliation: Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
authors.forename: Nevena
authors.initials: N
authors.lastname: MacKay
authors.affiliation: Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada. Electronic address: Annette.feigenbaum@sickkids.ca.
authors.forename: Annette
authors.initials: A
authors.lastname: Feigenbaum
authors.affiliation: Department of Pediatrics, McMaster University Medical Center, Hamilton, ON L8N 3Z5, Canada. Electronic address: tarnopol@mcmaster.ca.
authors.forename: Mark
authors.initials: M
authors.lastname: Tarnopolsky
authors.affiliation: Department of Radiology, The Hospital for Sick Children and University of Toronto, ON M5G 1X8, Canada. Electronic address: Susan.blaser@sickkids.ca.
authors.forename: Susan
authors.initials: S
authors.lastname: Blaser
authors.affiliation: Genetics & Genome Biology Program, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: Brian.robinson@sickkids.ca.
authors.forename: Brian H
authors.initials: BH
authors.lastname: Robinson
authors.affiliation: Genetics & Genome Biology Program, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada. Electronic address: Andreas.schulze@sickkids.ca.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schulze
mesh_terms: D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D007888:Leigh Disease / Q000235:genetics*; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D035781:Siblings
chemical_list: D009245:NADH Dehydrogenase; C492562:NDUFV2 protein, human
keywords: Complex I; Exome sequencing; Leigh syndrome; Mitochondria; NDUFV2