Clinical whole-exome sequencing for the diagnosis of mendelian disorders.
Clinical whole-exome sequencing for the diagnosis of mendelian disorders.
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DOI：
10.1056/nejmoa1306555
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发表时间：
2013-10-17
期刊：
影响因子：
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通讯作者：
Eng CM
中科院分区：
文献类型：
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作者：
Yang Y;Muzny DM;Reid JG;Bainbridge MN;Willis A;Ward PA;Braxton A;Beuten J;Xia F;Niu Z;Hardison M;Person R;Bekheirnia MR;Leduc MS;Kirby A;Pham P;Scull J;Wang M;Ding Y;Plon SE;Lupski JR;Beaudet AL;Gibbs RA;Eng CM
全外显子组测序是一种诊断方法，用于识别疑似遗传性疾病患者的分子缺陷。我们在经过认证的临床实验室中开发了全外显子组测序的技术、生物信息学、解释和验证流程，以识别患者疾病表型背后的序列变异。我们提供了前 250 名先证者的数据，转诊医生为其安排了全外显子组测序。患者表现出一系列表型，提示潜在的遗传原因。大约 80% 是具有神经表型的儿童。保险范围与已建立的基因测试的保险范围类似。我们在 250 名患者中鉴定出 86 个突变等位基因，这些基因极有可能与 62 名患者致病，实现了 25% 的分子诊断率（95% 置信区间，20 至 31）。在62名患者中，33名患有常染色体显性遗传疾病，16名患有常染色体隐性遗传疾病，9名患有X连锁疾病。共有 4 名先证者接受了两项不重叠的分子诊断，这可能对基于病史和体格检查做出的临床诊断提出了挑战。总共 83% 的常染色体显性突变等位基因和 40% 的 X 连锁突变等位基因是从头发生的。复发性临床表型发生在具有突变的患者中，这些突变很可能是导致遗传异质性疾病的相同基因和不同基因的致病原因。全外显子组测序在转诊评估可能的遗传状况的连续患者中发现了 25% 的潜在遗传缺陷。 （由国家人类基因组研究所资助。）
Whole-exome sequencing is a diagnostic approach for the identification of molecular defects in patients with suspected genetic disorders. We developed technical, bioinformatic, interpretive, and validation pipelines for whole-exome sequencing in a certified clinical laboratory to identify sequence variants underlying disease phenotypes in patients. We present data on the first 250 probands for whom referring physicians ordered whole-exome sequencing. Patients presented with a range of phenotypes suggesting potential genetic causes. Approximately 80% were children with neurologic pheno-types. Insurance coverage was similar to that for established genetic tests. We identified 86 mutated alleles that were highly likely to be causative in 62 of the 250 patients, achieving a 25% molecular diagnostic rate (95% confidence interval, 20 to 31). Among the 62 patients, 33 had autosomal dominant disease, 16 had auto-somal recessive disease, and 9 had X-linked disease. A total of 4 probands received two nonoverlapping molecular diagnoses, which potentially challenged the clinical diagnosis that had been made on the basis of history and physical examination. A total of 83% of the autosomal dominant mutant alleles and 40% of the X-linked mutant alleles occurred de novo. Recurrent clinical phenotypes occurred in patients with mutations that were highly likely to be causative in the same genes and in different genes responsible for genetically heterogeneous disorders. Whole-exome sequencing identified the underlying genetic defect in 25% of consecutive patients referred for evaluation of a possible genetic condition. (Funded by the National Human Genome Research Institute.)