Identification of Medically Actionable Secondary Findings in the 1000 Genomes.
Identification of Medically Actionable Secondary Findings in the 1000 Genomes.
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DOI：
10.1371/journal.pone.0135193
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Bierut LJ
中科院分区：
文献类型：
--
作者：
Olfson E;Cottrell CE;Davidson NO;Gurnett CA;Heusel JW;Stitziel NO;Chen LS;Hartz S;Nagarajan R;Saccone NL;Bierut LJ
美国医学遗传学和基因组学学会(ACMG)建议临床测序实验室返回与医学上可操作的疾病相关的56个基因的二次发现。我们的目标是应用一种符合临床标准的系统、严格的方法，使用不同的测序参考样本来估计与此类疾病相关的致病变异的流行率。56个ACMG基因的候选变异是从1000个基因组数据库的第一阶段中挑选出来的，该数据库包含来自世界各地的1092个无关个体的测序信息。使用人类基因突变数据库(HGMD)专业版筛选这些变异，定义参数，通过文献回顾进行评估，并由临床实验室专家和专家内科医生进行检查。从56个基因中提取了70,000多个遗传变异，过滤发现了237个变异，这些变异被HGMD专业人员注释为疾病。文献综述和专家评估确定这些变异中有7个是致病的或可能是致病的。此外，另外5个在HGMD专业人员中未被列为致病原因的截断变异被鉴定为可能的致病因素。这12个二次发现与可以为医学后续治疗提供信息的疾病相关，包括癌症易感综合征、心脏疾病和家族性高胆固醇血症。已确定的医学上可操作的发现大多发生在欧洲(5/379)和美洲(4/181)血统群体的个人身上，亚洲(2/286)和非洲(1/246)血统群体的发现较少。我们的结果表明，在不同的参考样本中，大约1%(12/1092)的个体可以识别出与医学相关的次要发现。随着临床测序实验室继续执行ACMG的建议，我们的结果强调，至少可以选择一小部分潜在的重要二次发现进行返回。我们的结果还证实，研究不足的人群不会从基因组药物中获得相应的好处，这突显了在这些人群中继续研究遗传病的必要性。
The American College of Medical Genetics and Genomics (ACMG) recommends that clinical sequencing laboratories return secondary findings in 56 genes associated with medically actionable conditions. Our goal was to apply a systematic, stringent approach consistent with clinical standards to estimate the prevalence of pathogenic variants associated with such conditions using a diverse sequencing reference sample. Candidate variants in the 56 ACMG genes were selected from Phase 1 of the 1000 Genomes dataset, which contains sequencing information on 1,092 unrelated individuals from across the world. These variants were filtered using the Human Gene Mutation Database (HGMD) Professional version and defined parameters, appraised through literature review, and examined by a clinical laboratory specialist and expert physician. Over 70,000 genetic variants were extracted from the 56 genes, and filtering identified 237 variants annotated as disease causing by HGMD Professional. Literature review and expert evaluation determined that 7 of these variants were pathogenic or likely pathogenic. Furthermore, 5 additional truncating variants not listed as disease causing in HGMD Professional were identified as likely pathogenic. These 12 secondary findings are associated with diseases that could inform medical follow-up, including cancer predisposition syndromes, cardiac conditions, and familial hypercholesterolemia. The majority of the identified medically actionable findings were in individuals from the European (5/379) and Americas (4/181) ancestry groups, with fewer findings in Asian (2/286) and African (1/246) ancestry groups. Our results suggest that medically relevant secondary findings can be identified in approximately 1% (12/1092) of individuals in a diverse reference sample. As clinical sequencing laboratories continue to implement the ACMG recommendations, our results highlight that at least a small number of potentially important secondary findings can be selected for return. Our results also confirm that understudied populations will not reap proportionate benefits of genomic medicine, highlighting the need for continued research efforts on genetic diseases in these populations.