Carrier testing for severe childhood recessive diseases by next-generation sequencing.
Carrier testing for severe childhood recessive diseases by next-generation sequencing.
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DOI：
10.1126/scitranslmed.3001756
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发表时间：
2011-01-12
影响因子：
17.1
通讯作者：
Kingsmore SF
中科院分区：
文献类型：
--
作者：
Bell CJ;Dinwiddie DL;Miller NA;Hateley SL;Ganusova EE;Mudge J;Langley RJ;Zhang L;Lee CC;Schilkey FD;Sheth V;Woodward JE;Peckham HE;Schroth GP;Kim RW;Kingsmore SF
在7028种疑似孟德尔遗传的疾病中，有1139种是隐性的，并且有确定的分子基础。虽然个别罕见，孟德尔疾病共同占婴儿死亡率的约20%和儿科住院的约10%。孕前筛查，加上对携带者的遗传咨询，已经导致几种严重的隐性疾病的发病率显着下降，包括泰-萨克斯病和囊性纤维化。然而，迄今为止，将孕前筛查扩展到大多数严重疾病基因是不切实际的。在这里，我们报告了448例严重隐性儿童疾病的孕前携带者筛查。而不是昂贵的，完整的人类基因组测序，从437个靶基因的7717个区域通过杂交捕获或微滴聚合酶链反应富集，通过下一代测序（NGS）测序的深度高达2.7千兆碱基，并与严格的生物信息学过滤器进行评估。在160×平均靶覆盖率下，93%的核苷酸具有至少20×覆盖率，突变检测/基因分型对置换、插入/缺失、剪接和总缺失突变以及单核苷酸多态性具有约95%的灵敏度和约100%的特异性。在104个无关的DNA样本中，严重的儿科隐性突变的平均基因组携带者负担为2.8，范围为0至7。测序样本中突变的分布似乎是随机的。在文献中引用的突变中，有27%被发现是常见的多态性或错误注释，这强调了需要更好的突变数据库作为全面的携带者检测策略的一部分。考虑到携带者负担的大小和与治疗这些疾病相比较低的检测成本，通过NGS对普通人群进行携带者筛查可能是降低严重隐性儿童疾病发病率和改善与严重隐性儿童疾病相关的痛苦的经济方式。
Of 7028 disorders with suspected Mendelian inheritance, 1139 are recessive and have an established molecular basis. Although individually uncommon, Mendelian diseases collectively account for ~20% of infant mortality and ~10% of pediatric hospitalizations. Preconception screening, together with genetic counseling of carriers, has resulted in remarkable declines in the incidence of several severe recessive diseases including Tay-Sachs disease and cystic fibrosis. However, extension of preconception screening to most severe disease genes has hitherto been impractical. Here, we report a preconception carrier screen for 448 severe recessive childhood diseases. Rather than costly, complete sequencing of the human genome, 7717 regions from 437 target genes were enriched by hybrid capture or microdroplet polymerase chain reaction, sequenced by next-generation sequencing (NGS) to a depth of up to 2.7 gigabases, and assessed with stringent bioinformatic filters. At a resultant 160× average target coverage, 93% of nucleotides had at least 20× coverage, and mutation detection/genotyping had ~95% sensitivity and ~100% specificity for substitution, insertion/deletion, splicing, and gross deletion mutations and single-nucleotide polymorphisms. In 104 unrelated DNA samples, the average genomic carrier burden for severe pediatric recessive mutations was 2.8 and ranged from 0 to 7. The distribution of mutations among sequenced samples appeared random. Twenty-seven percent of mutations cited in the literature were found to be common polymorphisms or misannotated, underscoring the need for better mutation databases as part of a comprehensive carrier testing strategy. Given the magnitude of carrier burden and the lower cost of testing compared to treating these conditions, carrier screening by NGS made available to the general population may be an economical way to reduce the incidence of and ameliorate suffering associated with severe recessive childhood disorders.
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DOI：
10.1007/s11568-010-9137-y
发表时间：
2009-12
期刊：
The HUGO journal
影响因子：
--
作者：
Hu, Hao;Wrogemann, Klaus;Kalscheuer, Vera;Tzschach, Andreas;Richard, Hugues;Haas, Stefan A;Menzel, Corinna;Bienek, Melanie;Froyen, Guy;Raynaud, Martine;Van Bokhoven, Hans;Chelly, Jamel;Ropers, Hilger;Chen, Wei
通讯作者：
Chen, Wei
DOI：
10.1073/pnas.0702165104
发表时间：
2007-05-29
影响因子：
11.1
作者：
Dahl, Fredrik;Stenberg, Johan;Ji, Hanlee
通讯作者：
Ji, Hanlee
影响因子：
7.2
作者：
通讯作者：
--
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.86.6.1919
发表时间：
1989-03-01
影响因子：
11.1
作者：
GIBBS, RA;NGUYEN, PN;CASKEY, CT
通讯作者：
CASKEY, CT