一项新的研究报告说，一种新型的遗传学测试可被医生常规地用来在夫妇有孩子之前筛检严重的隐性遗传性儿童疾病。 将这种技术与遗传咨询相结合，它可降低严重隐性儿童遗传性疾病的发病率并帮助在新生儿中加速对这些疾病的诊断。 然而，在普通大众中开展该妊娠前疾病携带者筛检这样一种测试的心理负担以及与生殖动力学相关的其它问题需要得到彻底的解决。 就个人来说，遗传性儿童疾病在普通大众中并不常见，但这些疾病占了所有婴儿死亡中的大约20%以及所有儿科疾病住院中的10%。 在过去的数十年中，有超过一千个与这些疾病有关的基因已经被找到。但在美国，只有5种疾病被建议在特定人群中进行孕前筛检测试，它们是：在选择性个体中的脆性Ｘ综合征、在白种人中的囊性纤维化以及在阿什克纳齐犹太后裔中的泰-萨克斯疾病（以及另外两种疾病）。
如今，Stephen Kingsmore及其同事研发出了一种孕前疾病携带者的测试，它可以同时对数百个DNA样品进行448种隐性遗传性儿童疾病的筛检。 该测试是基于一种各技术的组合，其中包括靶基因的捕捉和富集、新一代测序技术以及复杂精密的生物信息学分析。 用这种新的平台来筛检大约100名不相关的个体，研究人员发现，平均来说，每一位被测试者带有2或3种严重儿童疾病的突变基因。 他们还发现，在常用数据库中的大约10%的疾病基因突变是不正确的，提示需要对疾病基因突变数据库做仔细的审查。 尽管文章的作者承认，他们的数据只是初步的，但他们指出，在一般人群中的2至3种基因突变的表观随机分布是应该对每个人进行综合性孕前筛检测试的证据，而不只是在标靶人群中对少数特定疾病进行筛检。 一则相关的观点栏目回顾了人们为了对人类生殖提供资讯而分析人类基因组的历史，它还触及了该项研究的某些更宽泛的社会学蕴涵。 （生物谷 Bioon.com）
生物谷推荐原文出处：
Sci Transl Med DOI: 10.1126/scitranslmed.3001756
Carrier Testing for Severe Childhood Recessive Diseases by Next-Generation Sequencing
Callum J. Bell1,*, Darrell L. Dinwiddie1,2,*, Neil A. Miller1,2, Shannon L. Hateley1, Elena E. Ganusova1, Joann Mudge1, Ray J. Langley1, Lu Zhang3, Clarence C. Lee4, Faye D. Schilkey1, Vrunda Sheth4, Jimmy E. Woodward1, Heather E. Peckham4, Gary P. Schroth3, Ryan W. Kim1 and Stephen F. Kingsmore1,2,?
1National Center for Genome Resources, Santa Fe, NM 87505, USA.
2Children’s Mercy Hospital, Kansas City, MO 64108, USA.
3Illumina Inc., Hayward, CA 94545, USA.
4Life Technologies, Beverley, MA 01915, USA.
Abstract
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.
