Exome Sequencing and the Management of Neurometabolic Disorders.
Exome Sequencing and the Management of Neurometabolic Disorders.
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DOI：
10.1056/nejmoa1515792
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发表时间：
2016-06-09
期刊：
影响因子：
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通讯作者：
van Karnebeek CD
中科院分区：
文献类型：
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作者：
Tarailo-Graovac M;Shyr C;Ross CJ;Horvath GA;Salvarinova R;Ye XC;Zhang LH;Bhavsar AP;Lee JJ;Drögemöller BI;Abdelsayed M;Alfadhel M;Armstrong L;Baumgartner MR;Burda P;Connolly MB;Cameron J;Demos M;Dewan T;Dionne J;Evans AM;Friedman JM;Garber I;Lewis S;Ling J;Mandal R;Mattman A;McKinnon M;Michoulas A;Metzger D;Ogunbayo OA;Rakic B;Rozmus J;Ruben P;Sayson B;Santra S;Schultz KR;Selby K;Shekel P;Sirrs S;Skrypnyk C;Superti-Furga A;Turvey SE;Van Allen MI;Wishart D;Wu J;Wu J;Zafeiriou D;Kluijtmans L;Wevers RA;Eydoux P;Lehman AM;Vallance H;Stockler-Ipsiroglu S;Sinclair G;Wasserman WW;van Karnebeek CD
全外显子组测序改变了罕见疾病的基因发现和诊断。转化为改善疾病的治疗是具有挑战性的，特别是对于智力发育障碍。然而，例外的是先天性代谢缺陷，因为这些疾病中的许多对靶向分子或细胞水平的病理生理特征的治疗有反应。为了揭示潜在的可治疗的先天性代谢缺陷的遗传基础，我们通过半自动化生物信息学管道将深度临床表型（患者临床和生化表型的离散组分的综合表征）与全外显子组测序分析相结合，连续招募患有智力发育障碍和原因不明的代谢表型的患者。我们对从47个先证者获得的样品进行了全外显子组测序。在这些患者中，6例被排除，包括1例退出研究的患者。其余41名先证者的父母主要是欧洲血统的非血亲。在37个先证者中，我们确定了2个新涉及疾病的基因，9个候选基因，22个新发现表型的已知基因和9个预期表型的基因的变体;在大多数基因中，变体被归类为致病性或可能致病性。复杂的表型的患者在五个家庭的解释共存的单基因条件。我们在41名先证者中的28名（68%）中获得了诊断。在18例患者（44%）中进行了靶向干预试验。在41名患有智力发育障碍和不明原因的代谢异常的先证者中进行深度表型分析和全外显子组测序，导致68%的诊断，11个新涉及神经代谢疾病的候选基因的鉴定，以及44%的遗传咨询以外的治疗变化。（由BC儿童医院基金会和其他机构资助。
Whole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level. To uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patient’s clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes. We performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 probands had been born to predominantly nonconsanguineous parents of European descent. In 37 probands, we identified variants in 2 genes newly implicated in disease, 9 candidate genes, 22 known genes with newly identified phenotypes, and 9 genes with expected phenotypes; in most of the genes, the variants were classified as either pathogenic or probably pathogenic. Complex phenotypes of patients in five families were explained by coexisting monogenic conditions. We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%). Deep phenotyping and whole-exome sequencing in 41 probands with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%. (Funded by BC Children’s Hospital Foundation and others.)