Rapid identification of a novel complex I MT-ND3 m.10134C>A mutation in a Leigh syndrome patient

Miller, David K, Menezes, Minal J., Simons, Cas, Riley, Lisa G., Cooper, Sandra T., Grimmond, Sean M., Thorburn, David R., Christodoulou, John and Taft, Ryan J. (2014) Rapid identification of a novel complex I MT-ND3 m.10134C>A mutation in a Leigh syndrome patient. PLoS One, 9 8: e104879.1-e104879.6. doi:10.1371/journal.pone.0104879

Author Miller, David K
Menezes, Minal J.
Simons, Cas
Riley, Lisa G.
Cooper, Sandra T.
Grimmond, Sean M.
Thorburn, David R.
Christodoulou, John
Taft, Ryan J.
Title Rapid identification of a novel complex I MT-ND3 m.10134C>A mutation in a Leigh syndrome patient
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2014-08-12
Sub-type Article (original research)
DOI 10.1371/journal.pone.0104879
Open Access Status DOI
Volume 9
Issue 8
Start page e104879.1
End page e104879.6
Total pages 6
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Collection year 2015
Language eng
Abstract Leigh syndrome (LS) is a rare progressive multi-system neurodegenerative disorder, the genetics of which is frequently difficult to resolve. Rapid determination of the genetic etiology of LS in a 5-year-old girl facilitated inclusion in Edison Pharmaceutical's phase 2B clinical trial of EPI-743. SNP-arrays and high-coverage whole exome sequencing were performed on the proband, both parents and three unaffected siblings. Subsequent multi-tissue targeted high-depth mitochondrial sequencing was performed using custom long-range PCR amplicons. Tissue-specific mutant load was also assessed by qPCR. Complex I was interrogated by spectrophotometric enzyme assays and Western Blot. No putatively causal mutations were identified in nuclear-encoded genes. Analysis of low-coverage off-target mitochondrial reads revealed a previously unreported mitochondrial mutation in the proband in MT-ND3 (m.10134C>A, p.Q26K), a Complex I mitochondrial gene previously associated with LS. Targeted investigations demonstrated that this mutation was 1% heteroplasmic in the mother's blood and homoplasmic in the proband's blood, fibroblasts, liver and muscle. Enzyme assays revealed decreased Complex I activity. The identification of this novel LS MT-ND3 variant, the genomics of which was accomplished in less than 3.5 weeks, indicates that rapid genomic approaches may prove useful in time-sensitive cases with an unresolved genetic diagnosis.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
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