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Statements

Subject Item
n2:RIV%2F00064165%3A_____%2F12%3A12480%21RIV13-MZ0-00064165
rdf:type
n6:Vysledek skos:Concept
rdfs:seeAlso
http://dx.doi.org/10.1136/jmedgenet-2012-100846
dcterms:description
Background 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. Methods 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. Results 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. Conclusion 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. Background 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. Methods 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. Results 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. Conclusion 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.
dcterms:title
Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing
skos:prefLabel
Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing
skos:notation
RIV/00064165:_____/12:12480!RIV13-MZ0-00064165
n6:predkladatel
n13:ico%3A00064165
n3:aktivita
n7:V
n3:aktivity
V
n3:cisloPeriodika
4
n3:dodaniDat
n14:2013
n3:domaciTvurceVysledku
n12:5315263 n12:6270875 n12:1045261
n3:druhVysledku
n16:J
n3:duvernostUdaju
n18:S
n3:entitaPredkladatele
n17:predkladatel
n3:idSjednocenehoVysledku
151535
n3:idVysledku
RIV/00064165:_____/12:12480
n3:jazykVysledku
n15:eng
n3:klicovaSlova
leigh-syndrome; mutations; electrophoresis; identification; fibroblasts; disorders; variants; subunits; patient; genes
n3:klicoveSlovo
n8:fibroblasts n8:identification n8:variants n8:electrophoresis n8:patient n8:genes n8:mutations n8:disorders n8:leigh-syndrome n8:subunits
n3:kodStatuVydavatele
GB - Spojené království Velké Británie a Severního Irska
n3:kontrolniKodProRIV
[3B2D61ED6C1E]
n3:nazevZdroje
Journal of Medical Genetics
n3:obor
n11:EB
n3:pocetDomacichTvurcuVysledku
3
n3:pocetTvurcuVysledku
28
n3:rokUplatneniVysledku
n14:2012
n3:svazekPeriodika
49
n3:tvurceVysledku
Wilichowski, E. Zeviani, M. Sperl, W. Plecko, B. Kuhn, K. A. Haack, T.B. Hansíková, Hana Gorza, M. Haberberger, B. Wittig, I. Klopstock, T. Schuelke, M. Tesařová, Markéta Freisinger, P. Hennermann, J. B. Meitinger, T. Frisch, E. M. Hoffmann, G. F. Strecker, V. Herberg, U. Zeman, Jiří Wieland, T. Ahting, U. Iuso, A. Strom, T. M. Prokisch, H. Mayr, J. A Graf, E.
n3:wos
000302789800011
s:issn
0022-2593
s:numberOfPages
7