一項(xiàng)新的研究報(bào)告說，一種新型的遺傳學(xué)測試可被醫(yī)生常規(guī)地用來在夫婦有孩子之前篩檢嚴(yán)重的隱性遺傳性兒童疾病,。 將這種技術(shù)與遺傳咨詢相結(jié)合，它可降低嚴(yán)重隱性兒童遺傳性疾病的發(fā)病率并幫助在新生兒中加速對(duì)這些疾病的診斷,。 然而,，在普通大眾中開展該妊娠前疾病攜帶者篩檢這樣一種測試的心理負(fù)擔(dān)以及與生殖動(dòng)力學(xué)相關(guān)的其它問題需要得到徹底的解決。 就個(gè)人來說,，遺傳性兒童疾病在普通大眾中并不常見,，但這些疾病占了所有嬰兒死亡中的大約20%以及所有兒科疾病住院中的10%,。 在過去的數(shù)十年中，有超過一千個(gè)與這些疾病有關(guān)的基因已經(jīng)被找到,。但在美國,，只有5種疾病被建議在特定人群中進(jìn)行孕前篩檢測試，它們是：在選擇性個(gè)體中的脆性Ｘ綜合征,、在白種人中的囊性纖維化以及在阿什克納齊猶太后裔中的泰-薩克斯疾?。ㄒ约傲硗鈨煞N疾病）,。
如今,，Stephen Kingsmore及其同事研發(fā)出了一種孕前疾病攜帶者的測試，它可以同時(shí)對(duì)數(shù)百個(gè)DNA樣品進(jìn)行448種隱性遺傳性兒童疾病的篩檢,。 該測試是基于一種各技術(shù)的組合,，其中包括靶基因的捕捉和富集、新一代測序技術(shù)以及復(fù)雜精密的生物信息學(xué)分析,。 用這種新的平臺(tái)來篩檢大約100名不相關(guān)的個(gè)體,，研究人員發(fā)現(xiàn)，平均來說,，每一位被測試者帶有2或3種嚴(yán)重兒童疾病的突變基因,。 他們還發(fā)現(xiàn)，在常用數(shù)據(jù)庫中的大約10%的疾病基因突變是不正確的,，提示需要對(duì)疾病基因突變數(shù)據(jù)庫做仔細(xì)的審查,。 盡管文章的作者承認(rèn)，他們的數(shù)據(jù)只是初步的,，但他們指出,，在一般人群中的2至3種基因突變的表觀隨機(jī)分布是應(yīng)該對(duì)每個(gè)人進(jìn)行綜合性孕前篩檢測試的證據(jù)，而不只是在標(biāo)靶人群中對(duì)少數(shù)特定疾病進(jìn)行篩檢,。 一則相關(guān)的觀點(diǎn)欄目回顧了人們?yōu)榱藢?duì)人類生殖提供資訊而分析人類基因組的歷史,，它還觸及了該項(xiàng)研究的某些更寬泛的社會(huì)學(xué)蘊(yùn)涵。 （生物谷 Bioon.com）
生物谷推薦原文出處：
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.
