PharmGKB summary

Barbarino, Julia M.; McGregor, Tracy L.; Altman, Russ B.; Klein, Teri E.

doi:10.1097/fpc.0000000000000247

Cited by 19 publications

(12 citation statements)

References 112 publications

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“…Overall, we found 0.4% prevalence (1:240; 0.92% in research samples and 0.24% in the high-quality clinical samples) in our study with mainly Spanish individuals. For MT-RNR1 m.1494C>T and 1095T>C, also associated with nonsyndromic hearing loss in the presence of aminoglycoside exposure [ 2 ], but less common than m.1555A>G, only one carrier individual was identified.…”

Section: Discussionmentioning

confidence: 99%

“…Characterization of mtDNA genetic variation using unintendedly produced off-target sequencing data can impulse the advancement of preemptive pharmacogenetic screening and the prevention of aminoglycoside-induced hearing loss, for example, in diagnostic WES in children with suspected genetic diseases [ 7 , 15 ]. In addition, our work provides the possibility of further exploring the relevance of this marker using available off-target NGS data in diverse clinical fields, including patients with tuberculosis, with cystic fibrosis, and surgical patients allergic to beta-lactam antibiotics or oncology (e.g., patients with febrile neutropenia caused by chemotherapy) [ 2 , 5 , 8 , 9 , 10 , 11 , 12 , 23 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…Specific variants in this gene increase the binding affinity of aminoglycosides to the mitochondrial ribosome and are highly susceptible to irreversible hearing loss after administration of aminoglycoside antibiotics, regardless of dose, length of treatment, or serum drug levels. The most frequent cause for this ototoxicity is the variant m.1555A>G. This variant has been associated with hearing loss after treatment with aminoglycosides (e.g., gentamicin, streptomycin, tobramycin, kanamycin) in pedigree studies and in individual cases in multiple populations, with nearly 100% of variant carriers who receive aminoglycoside developing hearing loss [ 2 , 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…In addition to m.1555A>G, other MT-RNR1 variants associated with this ototoxicity have been described [ 2 , 3 ]. Together with m.1555A>G, the associations of m.1494C>T and m.1095T>C mtDNA variants with aminoglycoside-induced hearing loss are well-supported within the literature, and together with m.1555A>G, are included in international pharmacogenetics databases (e.g., PharmGKB).…”

Section: Introductionmentioning

confidence: 99%

“…Together with m.1555A>G, the associations of m.1494C>T and m.1095T>C mtDNA variants with aminoglycoside-induced hearing loss are well-supported within the literature, and together with m.1555A>G, are included in international pharmacogenetics databases (e.g., PharmGKB). The number of MT-RNR1 variants with pharmacogenetic implications has been growing based on the increasing number of studies focused on patients with diverse clinical conditions who required treatment with aminoglycosides [ 6 ], showing a large spectrum of MT-RNR1 pharmacogenetic variation [ 2 , 3 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

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

Lanillos

Santos

Carcajona³

et al. 2020

JCM

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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.

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Section: Discussionmentioning

confidence: 99%