Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
N Engl J Med. 2013 Oct 17;369(16):1502-11. doi: 10.1056/NEJMoa1306555. Epub 2013 Oct 2.
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 phenotypes. 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 autosomal 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.).
全外显子组测序是一种用于鉴定疑似遗传疾病患者分子缺陷的诊断方法。
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、解释和验证管道，以鉴定导致患者疾病表型的序列变异。
我们展示了前 250 名先证者的测序数据，这些先证者的主治医生为其开了全外显子组测序。患者表现出一系列提示潜在遗传病因的表型。大约 80%是有神经表型的儿童。保险覆盖范围与既定的遗传测试相似。我们在 250 名患者中的 62 名中鉴定出了 86 个高度可能致病的突变等位基因，达到了 25%的分子诊断率（95%置信区间，20%至 31%）。在这 62 名患者中，33 名患有常染色体显性疾病，16 名患有常染色体隐性疾病，9 名患有 X 连锁疾病。共有 4 名患者接受了两个不重叠的分子诊断，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。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新生的。具有高度可能致病突变的患者会出现相同基因和负责遗传异质性疾病的不同基因的反复出现的临床表型。
全外显子组测序在连续接受评估可能遗传疾病的 25%患者中确定了潜在的遗传缺陷。（由国家人类基因组研究所资助）。
