Molecular findings among patients referred for clinical whole-exome sequencing.
Molecular findings among patients referred for clinical whole-exome sequencing.
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DOI：
10.1001/jama.2014.14601
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发表时间：
2014-11-12
影响因子：
120.7
通讯作者：
Eng, Christine M.
中科院分区：
文献类型：
--
作者：
Yang, Yaping;Muzny, Donna M.;Xia, Fan;Niu, Zhiyv;Person, Richard;Ding, Yan;Ward, Patricia;Braxton, Alicia;Wang, Min;Buhay, Christian;Veeraraghavan, Narayanan;Hawes, Alicia;Chiang, Theodore;Leduc, Magalie;Beuten, Joke;Zhang, Jing;He, Weimin;Scull, Jennifer;Willis, Alecia;Landsverk, Megan;Craigen, William J.;Bekheirnia, Mir Reza;Stray-Pedersen, Asbjorg;Liu, Pengfei;Wen, Shu;Alcaraz, Wendy;Cui, Hong;Walkiewicz, Magdalena;Reid, Jeffrey;Bainbridge, Matthew;Patel, Ankita;Boerwinkle, Eric;Beaudet, Arthur L.;Lupski, James R.;Plon, Sharon E.;Gibbs, Richard A.;Eng, Christine M.
临床全外显子组测序越来越多地用于疑似遗传性疾病患者的诊断评估。进行临床全外显子组测序，并报告（1）表型组间的分子诊断率，（2）导致疾病的遗传变异谱，（3）可采取医学行动的偶然发现（如引起马凡氏综合征的FBN 1突变）的患病率。在2012年6月至2014年8月期间对2000例连续患者进行临床全外显子组测序分析的观察性研究。全外显子组测序测试在美国的临床遗传学实验室进行。结果由美国医学遗传学和基因组学委员会认证的临床分子遗传学家报告。检查由患者的医生安排。患者主要为儿科患者（1756例[88%];平均年龄6岁; 888例女性[44%]，1101例男性[55%]和11例胎儿[1%性别未知]），表现出多种临床表现，最常见的包括神经系统功能障碍，如发育迟缓。全外显子组测序诊断率整体和表型类别，遗传模式，遗传事件谱，和报告的偶然发现。报告了504例患者（25.2%）的分子诊断，其中58%的诊断突变先前未报告。各表型的分子诊断率为143/526（27.2%; 95% CI，23.5%-31.2%），神经系统组，282/1147（24.6%; 95% CI，22.1%-27.2%），神经系统加其他器官系统组，30/83（36.1%; 95% CI，26.1%-47.5%），非神经系统组为49/244（20.1%; 95% CI，15.6%-25.8%）。527例分子诊断的孟德尔遗传模式包括280例（53.1%）常染色体显性遗传，181例（34.3%）常染色体隐性遗传（包括5例单亲二体性），65例（12.3%）X连锁遗传和1例（0.2%）线粒体遗传。在504例分子诊断患者中，23例（4.6%）具有由2个单基因缺陷导致的混合表型。自2011年以来，约30%的阳性病例携带疾病基因突变。在92名患者（4.6%）中，有95个与表型无关但对管理有直接影响的基因中的医学可操作的偶然发现，其中包括59名（3%）被美国医学遗传学和基因组学学院推荐报告的基因突变患者。全外显子组测序为25%的大型患者队列提供了潜在的分子诊断，这些患者被转诊用于评估疑似遗传疾病，包括检测罕见遗传事件和导致疾病的新突变。对于某些患者来说，全外显子组测序的产率可能比传统的分子诊断方法更具优势。
Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders. To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome. Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient’s physician. The patients were primarily pediatric (1756 [88%]; mean age, 6 years; 888 females [44%], 1101 males [55%], and 11 fetuses [1% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay. Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings. A molecular diagnosis was reported for 504 patients (25.2%) with 58% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2%; 95% CI, 23.5%–31.2%) for the neurological group, 282/1147 (24.6%; 95% CI, 22.1%–27.2%) for the neurological plus other organ systems group, 30/83 (36.1%; 95% CI, 26.1%–47.5%) for the specific neurological group, and 49/244 (20.1%; 95% CI, 15.6%–25.8%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1%) autosomal dominant, 181 (34.3%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3%) X-linked, and 1 (0.2%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6%) had blended phenotypes resulting from 2 single gene defects. About 30% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6%), including 59 patients (3%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics. Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.
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DOI：
10.1126/science.1215040
发表时间：
2012-02-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
MacArthur DG;Balasubramanian S;Frankish A;Huang N;Morris J;Walter K;Jostins L;Habegger L;Pickrell JK;Montgomery SB;Albers CA;Zhang ZD;Conrad DF;Lunter G;Zheng H;Ayub Q;DePristo MA;Banks E;Hu M;Handsaker RE;Rosenfeld JA;Fromer M;Jin M;Mu XJ;Khurana E;Ye K;Kay M;Saunders GI;Suner MM;Hunt T;Barnes IH;Amid C;Carvalho-Silva DR;Bignell AH;Snow C;Yngvadottir B;Bumpstead S;Cooper DN;Xue Y;Romero IG;1000 Genomes Project Consortium;Wang J;Li Y;Gibbs RA;McCarroll SA;Dermitzakis ET;Pritchard JK;Barrett JC;Harrow J;Hurles ME;Gerstein MB;Tyler-Smith C
通讯作者：
Tyler-Smith C
影响因子：
3
作者：
Reid JG;Carroll A;Veeraraghavan N;Dahdouli M;Sundquist A;English A;Bainbridge M;White S;Salerno W;Buhay C;Yu F;Muzny D;Daly R;Duyk G;Gibbs RA;Boerwinkle E
通讯作者：
Boerwinkle E
DOI：
10.1038/gim.2011.68
发表时间：
2012-04
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1038/gim.2013.73
发表时间：
2013-07
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
9.8
作者：
Lederer, Damien;Grisart, Bernard;Verellen-Dumoulin, Christine
通讯作者：
Verellen-Dumoulin, Christine