A Novel Approach for the Identification of Pharmacogenetic Variants in MT-RNR1 through Next-Generation Sequencing Off-Target Data

Specific genetic variants in the mitochondrially encoded 12S ribosomal RNA gene (MT-RNR1) cause aminoglycoside-induced irreversible hearing loss. Mitochondrial DNA is usually not included in targeted sequencing experiments; however, off-target data may deliver this information. Here, we extract MT-R...

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Published inJournal of clinical medicine Vol. 9; no. 7; p. 2082
Main Authors Lanillos, Javier, Santos, María, Carcajona, Marta, Roldan-Romero, Juan María, Martinez, Angel M., Calsina, Bruna, Monteagudo, María, Leandro-García, Luis Javier, Montero-Conde, Cristina, Cascón, Alberto, Maietta, Paolo, Alvarez, Sara, Robledo, Mercedes, Rodriguez-Antona, Cristina
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 02.07.2020
MDPI
Subjects
Bioinformatics
Cancer
Chromosomes
Genes
Genetic disorders
Genetic engineering
Genomes
Genotype & phenotype
Hearing loss
Mitochondrial DNA
United Kingdom > UK
United States > US
Online AccessGet full text
ISSN2077-0383
2077-0383
DOI10.3390/jcm9072082

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Abstract Specific genetic variants in the mitochondrially encoded 12S ribosomal RNA gene (MT-RNR1) cause aminoglycoside-induced irreversible hearing loss. Mitochondrial DNA is usually not included in targeted sequencing experiments; however, off-target data may deliver this information. Here, we extract MT-RNR1 genetic variation, including the most relevant ototoxicity variant m.1555A>G, using the off-target reads of 473 research samples, sequenced through a capture-based, custom-targeted panel and whole exome sequencing (WES), and of 1245 diagnostic samples with clinical WES. Sanger sequencing and fluorescence-based genotyping were used for genotype validation. There was a correlation between off-target reads and mitochondrial coverage (rcustomPanel = 0.39, p = 2 × 10−13 and rWES = 0.67, p = 7 × 10−21). The median read depth of MT-RNR1 m.1555 was similar to the average mitochondrial genome coverage, with saliva and blood samples giving comparable results. The genotypes from 415 samples, including three m.1555G carriers, were concordant with fluorescence-based genotyping data. In clinical WES, median MT-RNR1 coverage was 56×, with 90% of samples having ≥20 reads at m.1555 position, and one m.1494T and three m.1555G carriers were identified with no evidence for heteroplasmy. Altogether, this study shows that obtaining MT-RNR1 genotypes through off-target reads is an efficient strategy that can impulse preemptive pharmacogenetic screening of this mitochondrial gene.
AbstractList Specific genetic variants in the mitochondrially encoded 12S ribosomal RNA gene (MT-RNR1) cause aminoglycoside-induced irreversible hearing loss. Mitochondrial DNA is usually not included in targeted sequencing experiments; however, off-target data may deliver this information. Here, we extract MT-RNR1 genetic variation, including the most relevant ototoxicity variant m.1555A>G, using the off-target reads of 473 research samples, sequenced through a capture-based, custom-targeted panel and whole exome sequencing (WES), and of 1245 diagnostic samples with clinical WES. Sanger sequencing and fluorescence-based genotyping were used for genotype validation. There was a correlation between off-target reads and mitochondrial coverage (rcustomPanel = 0.39, p = 2 × 10-13 and rWES = 0.67, p = 7 × 10-21). The median read depth of MT-RNR1 m.1555 was similar to the average mitochondrial genome coverage, with saliva and blood samples giving comparable results. The genotypes from 415 samples, including three m.1555G carriers, were concordant with fluorescence-based genotyping data. In clinical WES, median MT-RNR1 coverage was 56×, with 90% of samples having ≥20 reads at m.1555 position, and one m.1494T and three m.1555G carriers were identified with no evidence for heteroplasmy. Altogether, this study shows that obtaining MT-RNR1 genotypes through off-target reads is an efficient strategy that can impulse preemptive pharmacogenetic screening of this mitochondrial gene.Specific genetic variants in the mitochondrially encoded 12S ribosomal RNA gene (MT-RNR1) cause aminoglycoside-induced irreversible hearing loss. Mitochondrial DNA is usually not included in targeted sequencing experiments; however, off-target data may deliver this information. Here, we extract MT-RNR1 genetic variation, including the most relevant ototoxicity variant m.1555A>G, using the off-target reads of 473 research samples, sequenced through a capture-based, custom-targeted panel and whole exome sequencing (WES), and of 1245 diagnostic samples with clinical WES. Sanger sequencing and fluorescence-based genotyping were used for genotype validation. There was a correlation between off-target reads and mitochondrial coverage (rcustomPanel = 0.39, p = 2 × 10-13 and rWES = 0.67, p = 7 × 10-21). The median read depth of MT-RNR1 m.1555 was similar to the average mitochondrial genome coverage, with saliva and blood samples giving comparable results. The genotypes from 415 samples, including three m.1555G carriers, were concordant with fluorescence-based genotyping data. In clinical WES, median MT-RNR1 coverage was 56×, with 90% of samples having ≥20 reads at m.1555 position, and one m.1494T and three m.1555G carriers were identified with no evidence for heteroplasmy. Altogether, this study shows that obtaining MT-RNR1 genotypes through off-target reads is an efficient strategy that can impulse preemptive pharmacogenetic screening of this mitochondrial gene.
Specific genetic variants in the mitochondrially encoded 12S ribosomal RNA gene ( MT-RNR1 ) cause aminoglycoside-induced irreversible hearing loss. Mitochondrial DNA is usually not included in targeted sequencing experiments; however, off-target data may deliver this information. Here, we extract MT-RNR1 genetic variation, including the most relevant ototoxicity variant m.1555A>G, using the off-target reads of 473 research samples, sequenced through a capture-based, custom-targeted panel and whole exome sequencing (WES), and of 1245 diagnostic samples with clinical WES. Sanger sequencing and fluorescence-based genotyping were used for genotype validation. There was a correlation between off-target reads and mitochondrial coverage (r customPanel = 0.39, p = 2 × 10 −13 and rWES = 0.67, p = 7 × 10 −21 ). The median read depth of MT-RNR1 m.1555 was similar to the average mitochondrial genome coverage, with saliva and blood samples giving comparable results. The genotypes from 415 samples, including three m.1555G carriers, were concordant with fluorescence-based genotyping data. In clinical WES, median MT-RNR1 coverage was 56×, with 90% of samples having ≥20 reads at m.1555 position, and one m.1494T and three m.1555G carriers were identified with no evidence for heteroplasmy. Altogether, this study shows that obtaining MT-RNR1 genotypes through off-target reads is an efficient strategy that can impulse preemptive pharmacogenetic screening of this mitochondrial gene.
Specific genetic variants in the mitochondrially encoded 12S ribosomal RNA gene (MT-RNR1) cause aminoglycoside-induced irreversible hearing loss. Mitochondrial DNA is usually not included in targeted sequencing experiments; however, off-target data may deliver this information. Here, we extract MT-RNR1 genetic variation, including the most relevant ototoxicity variant m.1555A>G, using the off-target reads of 473 research samples, sequenced through a capture-based, custom-targeted panel and whole exome sequencing (WES), and of 1245 diagnostic samples with clinical WES. Sanger sequencing and fluorescence-based genotyping were used for genotype validation. There was a correlation between off-target reads and mitochondrial coverage (rcustomPanel = 0.39, p = 2 × 10−13 and rWES = 0.67, p = 7 × 10−21). The median read depth of MT-RNR1 m.1555 was similar to the average mitochondrial genome coverage, with saliva and blood samples giving comparable results. The genotypes from 415 samples, including three m.1555G carriers, were concordant with fluorescence-based genotyping data. In clinical WES, median MT-RNR1 coverage was 56×, with 90% of samples having ≥20 reads at m.1555 position, and one m.1494T and three m.1555G carriers were identified with no evidence for heteroplasmy. Altogether, this study shows that obtaining MT-RNR1 genotypes through off-target reads is an efficient strategy that can impulse preemptive pharmacogenetic screening of this mitochondrial gene.
Author Leandro-García, Luis Javier
Santos, María
Cascón, Alberto
Carcajona, Marta
Martinez, Angel M.
Monteagudo, María
Montero-Conde, Cristina
Maietta, Paolo
Robledo, Mercedes
Calsina, Bruna
Rodriguez-Antona, Cristina
Lanillos, Javier
Roldan-Romero, Juan María
Alvarez, Sara
AuthorAffiliation 1 Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain; jlanillos@cnio.es (J.L.); msantosr@cnio.es (M.S.); jmroldan@cnio.es (J.M.R.-R.); ammontes@cnio.es (A.M.M.); bcalsina@cnio.es (B.C.); mmonteagudo@cnio.es (M.M.); ljleandro@cnio.es (L.J.L.-G.); cmontero@cnio.es (C.M.-C.); acascon@cnio.es (A.C.); mrobledo@cnio.es (M.R.)
2 Nimgenetics, 28049 Madrid, Spain; mcarcajona@nimgenetics.com (M.C.); pmaietta@nimgenetics.com (P.M.); salvarez@nimgenetics.com (S.A.)
3 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
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– name: 3 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
– name: 1 Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain; jlanillos@cnio.es (J.L.); msantosr@cnio.es (M.S.); jmroldan@cnio.es (J.M.R.-R.); ammontes@cnio.es (A.M.M.); bcalsina@cnio.es (B.C.); mmonteagudo@cnio.es (M.M.); ljleandro@cnio.es (L.J.L.-G.); cmontero@cnio.es (C.M.-C.); acascon@cnio.es (A.C.); mrobledo@cnio.es (M.R.)
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CitedBy_id crossref_primary_10_1093_jac_dkae106
crossref_primary_10_1016_j_therap_2024_05_006
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Snippet Specific genetic variants in the mitochondrially encoded 12S ribosomal RNA gene (MT-RNR1) cause aminoglycoside-induced irreversible hearing loss. Mitochondrial...
Specific genetic variants in the mitochondrially encoded 12S ribosomal RNA gene ( MT-RNR1 ) cause aminoglycoside-induced irreversible hearing loss....
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proquest
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SourceType Open Access Repository
Aggregation Database
Enrichment Source
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StartPage 2082
SubjectTerms Bioinformatics
Cancer
Chromosomes
Genes
Genetic disorders
Genetic engineering
Genomes
Genotype & phenotype
Hearing loss
Mitochondrial DNA
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Title A Novel Approach for the Identification of Pharmacogenetic Variants in MT-RNR1 through Next-Generation Sequencing Off-Target Data
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https://www.proquest.com/docview/2421117519
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