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start [2017/06/24 17:22]
bioadmin [6.3 线粒体变异]
start [2017/06/24 17:24]
bioadmin [6.4 药物基因组学]
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 Heteroplasmy or homoplasmy should be reported, along with an estimate of heteroplasmy of the variant if the test has   been validated to determine heteroplasmy levels. Heteroplasmy percentages in different tissue types may vary from the sample tested; therefore, low heteroplasmic levels also must be interpreted in the context of the tissue tested, and they may be meaningful only in the affected tissue such as muscle. Over 275 mitochondrial DNA variants relating to disease have been recorded (http://​mitomap.org/​bin/​view.pl/​MITOMAP/​WebHome). MitoMap is considered the main source of information related to mitochondrial variants as well as haplotypes. Other resources, such as frequency information (http://​www.mtdb.igp.uu.se/​),​ secondary structures, sequences, and alignment of mitochondrial transfer RNAs (http://​mamittrna.u-strasbg.fr/​),​ mitochondrial haplogroups (http://​www.phylotree.org/​)and other information (http://​www.mtdnacommunity.org/​default.aspx),​ may prove useful in interpreting mitochondrial variants. Heteroplasmy or homoplasmy should be reported, along with an estimate of heteroplasmy of the variant if the test has   been validated to determine heteroplasmy levels. Heteroplasmy percentages in different tissue types may vary from the sample tested; therefore, low heteroplasmic levels also must be interpreted in the context of the tissue tested, and they may be meaningful only in the affected tissue such as muscle. Over 275 mitochondrial DNA variants relating to disease have been recorded (http://​mitomap.org/​bin/​view.pl/​MITOMAP/​WebHome). MitoMap is considered the main source of information related to mitochondrial variants as well as haplotypes. Other resources, such as frequency information (http://​www.mtdb.igp.uu.se/​),​ secondary structures, sequences, and alignment of mitochondrial transfer RNAs (http://​mamittrna.u-strasbg.fr/​),​ mitochondrial haplogroups (http://​www.phylotree.org/​)and other information (http://​www.mtdnacommunity.org/​default.aspx),​ may prove useful in interpreting mitochondrial variants.
  
-如果已通过检测对异质性水平进行确定,应该对异质性或同质性,以及变异异质性的评估进行报道。不同组织类型的异质性百分比因检测样本的不同而有所改变,​ 因此,低异质性水平也必须结合所检测组织进行解读,且它们可能仅在受累及的组织中才是有意义的,如肌肉组织。超过275个与疾病相关的线粒体DNA变异已被记录(http://​mitomap.org/​bin/​view.pl/​MITOMAP/​WebHome)。MitoMap是线粒体变异及单倍型相关信息的主要来源。其他资源,如频率信息(http://​www.mtdb.igp.uu.se/​)、二级结构、序列和线粒体转运RNA的比对(http://​mamittrna.u-strasbg.fr/​)、线粒体单倍群(http://​www.phylotree.org/​)[35]和其他信息(http://​www.mtdnacommunity.org/​default.aspx),可能在解读线粒体变异时是有用的。+如果已通过检测对异质性水平进行确定,应该对异质性或同质性,以及变异异质性的评估进行报道。不同组织类型的异质性百分比因检测样本的不同而有所改变,​ 因此,低异质性水平也必须结合所检测组织进行解读,且它们可能仅在受累及的组织中才是有意义的,如肌肉组织。超过275个与疾病相关的线粒体DNA变异已被记录(http://​mitomap.org/​bin/​view.pl/​MITOMAP/​WebHome)。MitoMap是线粒体变异及单倍型相关信息的主要来源。其他资源,如频率信息(http://​www.mtdb.igp.uu.se/​)、二级结构、序列和线粒体转运RNA的比对(http://​mamittrna.u-strasbg.fr/​)、线粒体单倍群(http://​www.phylotree.org/​)和其他信息(http://​www.mtdnacommunity.org/​default.aspx),可能在解读线粒体变异时是有用的。
  
 Given the difficulty in assessing mitochondrial variants, a separate evidence checklist has not been included. However, any evidence needs to be applied with additional caution. The genes in the mitochondrial genome encode for transfer RNA as well as for protein; therefore, evaluating amino acid changes is relevant only for genes encoding proteins. Similarly, because many mitochondrial variants are missense variants, evidence criteria for truncating variants likely will not be helpful. Because truncating variants do not fit the known variant spectrum in most mitochondrial genes, their significance may be uncertain. Although mitochondrial variants are typically maternally inherited, they can be sporadic, yet de novo variants are difficult to assess because of heteroplasmy that may be below an assay’s detection level or different between tissues. The level of heteroplasmy may contribute to the variable expression and reduced penetrance that occurs within families. Nevertheless,​ there remains a lack of correlation between the percentage of heteroplasmy and disease severity. Muscle, liver, or urine may be additional specimen types useful for clinical evaluation. Undetected heteroplasmy may also affect outcomes of case, case–control,​ and familial concordance studies. In addition, functional studies are not readily available, although evaluating muscle morphology may be helpful (i.e., the presence of ragged red fibers). Frequency data and published studies demonstrating causality may often be the only assessable criteria on the checklist. An additional tool for mitochondrial diseases may be haplogroup analysis, but this may not represent a routine method that clinical laboratories have used, and the clinical correlation is not easy to interpret. Given the difficulty in assessing mitochondrial variants, a separate evidence checklist has not been included. However, any evidence needs to be applied with additional caution. The genes in the mitochondrial genome encode for transfer RNA as well as for protein; therefore, evaluating amino acid changes is relevant only for genes encoding proteins. Similarly, because many mitochondrial variants are missense variants, evidence criteria for truncating variants likely will not be helpful. Because truncating variants do not fit the known variant spectrum in most mitochondrial genes, their significance may be uncertain. Although mitochondrial variants are typically maternally inherited, they can be sporadic, yet de novo variants are difficult to assess because of heteroplasmy that may be below an assay’s detection level or different between tissues. The level of heteroplasmy may contribute to the variable expression and reduced penetrance that occurs within families. Nevertheless,​ there remains a lack of correlation between the percentage of heteroplasmy and disease severity. Muscle, liver, or urine may be additional specimen types useful for clinical evaluation. Undetected heteroplasmy may also affect outcomes of case, case–control,​ and familial concordance studies. In addition, functional studies are not readily available, although evaluating muscle morphology may be helpful (i.e., the presence of ragged red fibers). Frequency data and published studies demonstrating causality may often be the only assessable criteria on the checklist. An additional tool for mitochondrial diseases may be haplogroup analysis, but this may not represent a routine method that clinical laboratories have used, and the clinical correlation is not easy to interpret.
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 ==== 6.4 药物基因组学 ==== ==== 6.4 药物基因组学 ====
  
-Establishing the effects of variants in genes involved with drug metabolism is challenging,​ in part because a phenotype is only apparent upon exposure to a drug. Still, variants in genes related to drug efficacy and risk for adverse events have been described and are increasingly used in clinical care. Gene summaries and clinically relevant variants can be found in the Pharmacogenomics Knowledge Base (http://​www.pharmgkb. org/). Alleles and nomenclature for the cytochrome P450 gene family is available at http://​www.cypalleles.ki.se/​.Although the interpretation of PGx variants is beyond the scope of this document, we include a discussion of the challenges and distinctions associated with the interpretation and reporting of PGx results.+Establishing the effects of variants in genes involved with drug metabolism is challenging,​ in part because a phenotype is only apparent upon exposure to a drug. Still, variants in genes related to drug efficacy and risk for adverse events have been described and are increasingly used in clinical care. Gene summaries and clinically relevant variants can be found in the Pharmacogenomics Knowledge Base (http://​www.pharmgkb. org/). Alleles and nomenclature for the cytochrome P450 gene family is available at http://​www.cypalleles.ki.se/​. Although the interpretation of PGx variants is beyond the scope of this document, we include a discussion of the challenges and distinctions associated with the interpretation and reporting of PGx results.
  
 确认基因变异在药物代谢中的作用具有挑战性,部分原因在于其表型只有在接触药物后才得以显现。不过,临床上现已报告了各种与药物疗效和副作用风险相关的基因变异,且其数量仍然在不断增加。相关基因的汇总及其有临床意义的变异可查询药物基因组学知识库网站(http://​www.pharmgkb.org/​)。有关细胞色素P450基因家族等位基因及其命名可查询网站http://​www.cypalleles.ki.se/​。尽管解读药物基因组变异已超出了本文的范围,还是对与解读及报告药物基因组结果相关的挑战和鉴别进行了讨论。 确认基因变异在药物代谢中的作用具有挑战性,部分原因在于其表型只有在接触药物后才得以显现。不过,临床上现已报告了各种与药物疗效和副作用风险相关的基因变异,且其数量仍然在不断增加。相关基因的汇总及其有临床意义的变异可查询药物基因组学知识库网站(http://​www.pharmgkb.org/​)。有关细胞色素P450基因家族等位基因及其命名可查询网站http://​www.cypalleles.ki.se/​。尽管解读药物基因组变异已超出了本文的范围,还是对与解读及报告药物基因组结果相关的挑战和鉴别进行了讨论。