The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study.
The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study.
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早期，全面的基因组测试对新生儿糖尿病的临床护理的影响：一项国际队列研究。
DOI：
10.1016/s0140-6736(15)60098-8
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发表时间：
2015-09-05
期刊：
影响因子：
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通讯作者：
Hattersley AT
中科院分区：
文献类型：
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作者：
De Franco E;Flanagan SE;Houghton JA;Lango Allen H;Mackay DJ;Temple IK;Ellard S;Hattersley AT
传统的基因检测侧重于根据临床特征分析一个或几个基因;随着改进的测序方法能够同时分析几个基因，这种方法正在发生变化。新生儿糖尿病是由不同遗传原因定义的许多离散临床表型的呈现特征。遗传亚型定义治疗，对于大多数钾通道突变患者，磺脲类药物治疗可改善血液病控制。我们调查了早期全面检测所有已知的新生儿糖尿病遗传原因的效果。在这项大型国际队列研究中，我们研究了来自79个国家的6个月前诊断为糖尿病的新生儿糖尿病患者。我们通过全面的基因检测，包括桑格测序、6 q24甲基化分析和所有已知新生儿糖尿病基因的靶向下一代测序，确定了突变。在2000年1月至2013年8月期间，对1020名患者（571名男孩，449名女孩）进行了基因检测。钾通道基因突变是新生儿糖尿病最常见的原因（n=390），但在近亲家庭中发现的频率较低（近亲家庭为12%，非近亲家庭为46%; p<0.0001）。基因检测时糖尿病的中位持续时间从2005年前的4年多下降到2012年后的不到3个月。早期转介基因检测影响临床表型。在遗传学诊断为Wolcott-Rallison综合征的患者中，26例患者中有23例（88%）在诊断后3个月内接受了检测，而18例患者中有3例（17%）在诊断后4年（>4年; p<0.0001），其中骨骼和肝脏受累常见。同样，对于经基因诊断为短暂性新生儿糖尿病的患者，早期（<3个月）检测的101名患者中，只有10名（10%）的糖尿病缓解，而随后转诊的60名患者中，有60名（100%）（p<0·0001）。现在，患者在更接近新生儿糖尿病的表现时被转诊进行基因检测。对所有病因的全面检测在80%以上的病例中发现了因果突变。遗传结果预测了最佳的糖尿病治疗和相关特征的发展。这种模式代表了一种新的框架，为临床护理与遗传诊断之前的发展，临床特征和指导临床管理。Wellcome Trust和Diabetes UK。
Traditional genetic testing focusses on analysis of one or a few genes according to clinical features; this approach is changing as improved sequencing methods enable simultaneous analysis of several genes. Neonatal diabetes is the presenting feature of many discrete clinical phenotypes defined by different genetic causes. Genetic subtype defines treatment, with improved glycaemic control on sulfonylurea treatment for most patients with potassium channel mutations. We investigated the effect of early, comprehensive testing of all known genetic causes of neonatal diabetes. In this large, international, cohort study, we studied patients with neonatal diabetes diagnosed with diabetes before 6 months of age who were referred from 79 countries. We identified mutations by comprehensive genetic testing including Sanger sequencing, 6q24 methylation analysis, and targeted next-generation sequencing of all known neonatal diabetes genes. Between January, 2000, and August, 2013, genetic testing was done in 1020 patients (571 boys, 449 girls). Mutations in the potassium channel genes were the most common cause (n=390) of neonatal diabetes, but were identified less frequently in consanguineous families (12% in consanguineous families vs 46% in non-consanguineous families; p<0·0001). Median duration of diabetes at the time of genetic testing decreased from more than 4 years before 2005 to less than 3 months after 2012. Earlier referral for genetic testing affected the clinical phenotype. In patients with genetically diagnosed Wolcott-Rallison syndrome, 23 (88%) of 26 patients tested within 3 months from diagnosis had isolated diabetes, compared with three (17%) of 18 patients referred later (>4 years; p<0·0001), in whom skeletal and liver involvement was common. Similarly, for patients with genetically diagnosed transient neonatal diabetes, the diabetes had remitted in only ten (10%) of 101 patients tested early (<3 months) compared with 60 (100%) of the 60 later referrals (p<0·0001). Patients are now referred for genetic testing closer to their presentation with neonatal diabetes. Comprehensive testing of all causes identified causal mutations in more than 80% of cases. The genetic result predicts the best diabetes treatment and development of related features. This model represents a new framework for clinical care with genetic diagnosis preceding development of clinical features and guiding clinical management. Wellcome Trust and Diabetes UK.