Chip-based mtDNA mutation screening enables fast and reliable genetic diagnosis of OXPHOS patients

R.G. van Eijsden, M. Gerards, L.M. Eijssen, A.T. Hendrickx, R.J.E. Jongbloed, J.H. Wokke, R.Q. Hintzen, M.E. Rubio-Gozalbo, I.F. De Coo, E. Briem, V. Tiranti, H.J. Smeets

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Abstract

PURPOSE: Oxidative phosphorylation is under dual genetic control of the nuclear and the mitochondrial DNA (mtDNA). Oxidative phosphorylation disorders are clinically and genetically heterogeneous, which makes it difficult to determine the genetic defect, and symptom-based protocols which link clinical symptoms directly to a specific gene or mtDNA mutation are falling short. Moreover, approximately 25% of the pediatric patients with oxidative phosphorylation disorders is estimated to have mutations in the mtDNA and a standard screening approach for common mutations and deletions will only explain part of these cases. Therefore, we tested a new CHIP-based screening method for the mtDNA. METHODS: MitoChip (Affymetrix) resequencing was performed on three test samples and on 28 patient samples. RESULTS: Call rates were 94% on average and heteroplasmy detection levels varied from 5-50%. A genetic diagnosis can be made in almost one-quarter of the patients at a potential output of 8 complete mtDNA sequences every 4 days. Moreover, a number of potentially pathogenic unclassified variants (UV) were detected. CONCLUSIONS: The availability of long-range PCR protocols and the predominance of single nucleotide substitutions in the mtDNA make the resequencing CHIP a very fast and reliable method to screen the complete mtDNA for mutations.
Original languageEnglish
Pages (from-to)620-627
JournalGenetics in Medicine
Volume8
Issue number10
DOIs
Publication statusPublished - 1 Jan 2006

Cite this

van Eijsden, R.G. ; Gerards, M. ; Eijssen, L.M. ; Hendrickx, A.T. ; Jongbloed, R.J.E. ; Wokke, J.H. ; Hintzen, R.Q. ; Rubio-Gozalbo, M.E. ; De Coo, I.F. ; Briem, E. ; Tiranti, V. ; Smeets, H.J. / Chip-based mtDNA mutation screening enables fast and reliable genetic diagnosis of OXPHOS patients. In: Genetics in Medicine. 2006 ; Vol. 8, No. 10. pp. 620-627.
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abstract = "PURPOSE: Oxidative phosphorylation is under dual genetic control of the nuclear and the mitochondrial DNA (mtDNA). Oxidative phosphorylation disorders are clinically and genetically heterogeneous, which makes it difficult to determine the genetic defect, and symptom-based protocols which link clinical symptoms directly to a specific gene or mtDNA mutation are falling short. Moreover, approximately 25{\%} of the pediatric patients with oxidative phosphorylation disorders is estimated to have mutations in the mtDNA and a standard screening approach for common mutations and deletions will only explain part of these cases. Therefore, we tested a new CHIP-based screening method for the mtDNA. METHODS: MitoChip (Affymetrix) resequencing was performed on three test samples and on 28 patient samples. RESULTS: Call rates were 94{\%} on average and heteroplasmy detection levels varied from 5-50{\%}. A genetic diagnosis can be made in almost one-quarter of the patients at a potential output of 8 complete mtDNA sequences every 4 days. Moreover, a number of potentially pathogenic unclassified variants (UV) were detected. CONCLUSIONS: The availability of long-range PCR protocols and the predominance of single nucleotide substitutions in the mtDNA make the resequencing CHIP a very fast and reliable method to screen the complete mtDNA for mutations.",
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Chip-based mtDNA mutation screening enables fast and reliable genetic diagnosis of OXPHOS patients. / van Eijsden, R.G.; Gerards, M.; Eijssen, L.M.; Hendrickx, A.T.; Jongbloed, R.J.E.; Wokke, J.H.; Hintzen, R.Q.; Rubio-Gozalbo, M.E.; De Coo, I.F.; Briem, E.; Tiranti, V.; Smeets, H.J.

In: Genetics in Medicine, Vol. 8, No. 10, 01.01.2006, p. 620-627.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Chip-based mtDNA mutation screening enables fast and reliable genetic diagnosis of OXPHOS patients

AU - van Eijsden, R.G.

AU - Gerards, M.

AU - Eijssen, L.M.

AU - Hendrickx, A.T.

AU - Jongbloed, R.J.E.

AU - Wokke, J.H.

AU - Hintzen, R.Q.

AU - Rubio-Gozalbo, M.E.

AU - De Coo, I.F.

AU - Briem, E.

AU - Tiranti, V.

AU - Smeets, H.J.

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N2 - PURPOSE: Oxidative phosphorylation is under dual genetic control of the nuclear and the mitochondrial DNA (mtDNA). Oxidative phosphorylation disorders are clinically and genetically heterogeneous, which makes it difficult to determine the genetic defect, and symptom-based protocols which link clinical symptoms directly to a specific gene or mtDNA mutation are falling short. Moreover, approximately 25% of the pediatric patients with oxidative phosphorylation disorders is estimated to have mutations in the mtDNA and a standard screening approach for common mutations and deletions will only explain part of these cases. Therefore, we tested a new CHIP-based screening method for the mtDNA. METHODS: MitoChip (Affymetrix) resequencing was performed on three test samples and on 28 patient samples. RESULTS: Call rates were 94% on average and heteroplasmy detection levels varied from 5-50%. A genetic diagnosis can be made in almost one-quarter of the patients at a potential output of 8 complete mtDNA sequences every 4 days. Moreover, a number of potentially pathogenic unclassified variants (UV) were detected. CONCLUSIONS: The availability of long-range PCR protocols and the predominance of single nucleotide substitutions in the mtDNA make the resequencing CHIP a very fast and reliable method to screen the complete mtDNA for mutations.

AB - PURPOSE: Oxidative phosphorylation is under dual genetic control of the nuclear and the mitochondrial DNA (mtDNA). Oxidative phosphorylation disorders are clinically and genetically heterogeneous, which makes it difficult to determine the genetic defect, and symptom-based protocols which link clinical symptoms directly to a specific gene or mtDNA mutation are falling short. Moreover, approximately 25% of the pediatric patients with oxidative phosphorylation disorders is estimated to have mutations in the mtDNA and a standard screening approach for common mutations and deletions will only explain part of these cases. Therefore, we tested a new CHIP-based screening method for the mtDNA. METHODS: MitoChip (Affymetrix) resequencing was performed on three test samples and on 28 patient samples. RESULTS: Call rates were 94% on average and heteroplasmy detection levels varied from 5-50%. A genetic diagnosis can be made in almost one-quarter of the patients at a potential output of 8 complete mtDNA sequences every 4 days. Moreover, a number of potentially pathogenic unclassified variants (UV) were detected. CONCLUSIONS: The availability of long-range PCR protocols and the predominance of single nucleotide substitutions in the mtDNA make the resequencing CHIP a very fast and reliable method to screen the complete mtDNA for mutations.

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