Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Haack, TB; Haberberger, B; Frisch, EM; Wieland, T; Iuso, A; Gorza, M; Strecker, V; Graf, E; Mayr, JA; Herberg, U; Hennermann, JB; Klopstock, T; Kuhn, KA; Ahting, U; Sperl, W; Wilichowski, E; Hoffmann, GF; Tesarova, M; Hansikova, H; Zeman, J; Plecko, B; Zeviani, M; Wittig, I; Strom, TM; Schuelke, M; Freisinger, P; Meitinger, T; Prokisch, H.
Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing.
J Med Genet. 2012; 49(4): 277-283.
Doi: 10.1136/jmedgenet-2012-100846
Web of Science
PubMed
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- Co-Autor*innen der Med Uni Graz
- Plecko Barbara
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- Abstract:
- Next generation sequencing has become the core technology for gene discovery in rare inherited disorders. However, the interpretation of the numerous sequence variants identified remains challenging. We assessed the application of exome sequencing for diagnostics in complex I deficiency, a disease with vast genetic heterogeneity. Ten unrelated individuals with complex I deficiency were selected for exome sequencing and sequential bioinformatic filtering. Cellular rescue experiments were performed to verify pathogenicity of novel disease alleles. The first filter criterion was 'Presence of known pathogenic complex I deficiency variants'. This revealed homozygous mutations in NDUFS3 and ACAD9 in two individuals. A second criterion was 'Presence of two novel potentially pathogenic variants in a structural gene of complex I', which discovered rare variants in NDUFS8 in two unrelated individuals and in NDUFB3 in a third. Expression of wild-type cDNA in mutant cell lines rescued complex I activity and assembly, thus providing a functional validation of their pathogenicity. Using the third criterion 'Presence of two potentially pathogenic variants in a gene encoding a mitochondrial protein', loss-of-function mutations in MTFMT were discovered in two patients. In three patients the molecular genetic correlate remained unclear and follow-up analysis is ongoing. Appropriate in silico filtering of exome sequencing data, coupled with functional validation of new disease alleles, is effective in rapidly identifying disease-causative variants in known and new complex I associated disease genes.
- Find related publications in this database (using NLM MeSH Indexing)
- Amino Acid Substitution -
- Electron Transport Complex I - deficiency
- Electron Transport Complex I - genetics
- Exome -
- Gene Expression -
- Humans -
- Mitochondrial Diseases - diagnosis
- Mitochondrial Diseases - genetics
- Mutation -
- NADH Dehydrogenase - genetics
- Sequence Analysis, DNA -