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...

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Published in:European journal of paediatric neurology 2015-09, Vol.19 (5), p.525-532
Main Authors: Cameron, Jessie M, MacKay, Nevena, Feigenbaum, Annette, Tarnopolsky, Mark, Blaser, Susan, Robinson, Brian H, Schulze, Andreas
Format: Article
Language:English
Subjects:
Complex I
Exome - genetics
Exome sequencing
Female
Humans
Leigh Disease - genetics
Leigh syndrome
Mitochondria
Mutation
NADH Dehydrogenase - genetics
NDUFV2
Neurology
Pediatrics
Pedigree
Phenotype
Siblings
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Summary: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. Conclusion 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.
ISSN:1090-3798
1532-2130
DOI:10.1016/j.ejpn.2015.05.002