Rapid whole genome sequencing and precision neonatology.
Rapid whole genome sequencing and precision neonatology.
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DOI：
10.1053/j.semperi.2015.09.009
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发表时间：
2015-12
影响因子：
3.4
通讯作者：
Kingsmore SF
中科院分区：
文献类型：
--
作者：
Petrikin JE;Willig LK;Smith LD;Kingsmore SF
传统上，基因检测速度太慢，或者被认为对危重新生儿的初始管理不切实际。技术进步使人们能够在不到50小时的时间内对新生儿的整个基因组进行测序和解释。随着检测成本和速度的降低，新生儿全基因组测序(WGS)在急性和潜伏性遗传病中的效用增加。通过分析整个基因组，可以同时评估目前已确定的5430种单基因疾病。当应用于IV级新生儿重症监护病房中选定的患病婴儿人群时，WGS在57%的患者中产生了一种致病遗传病的诊断。这些诊断可能导致临床治疗的变化，从过渡到对一致致命的情况进行姑息治疗，到改变或开始内科或外科治疗以改善其他患者的结果。因此，在急性表现时制定2天的WGS为早期实施精确医学打开了可能性。这一实施可能会为早期介入治疗创造机会，这种治疗往往是新颖的或标签外的，可能会改变患有致命疾病的婴儿的疾病轨迹。快速WGS和精确医学的广泛应用将引发与解释未知意义的变异、发现与成人发病情况和携带者状况有关的偶然发现以及实施风险和益处鲜为人知的医疗疗法有关的伦理问题。尽管有这些挑战，但精确新生儿学在降低与新生儿发病的遗传病相关的婴儿死亡率和促进父母关于过渡到姑息治疗的决策方面都具有巨大的潜力。
Traditionally, genetic testing has been too slow or perceived to be impractical to initial management of the critically ill neonate. Technological advances have led to the ability to sequence and interpret the entire genome of a neonate in less than 50 hours. As the cost and speed of testing decreases, the utility of whole genome sequencing (WGS) of neonates for acute and latent genetic illness increases. Analyzing the entire genome allows for concomitant evaluation of the currently identified 5,430 single gene diseases. When applied to a select population of ill infants in a level IV neonatal intensive care unit, WGS yielded a diagnosis of a causative genetic disease in 57% of patients. These diagnoses may lead to clinical management changes ranging from transition to palliative care for uniformly lethal conditions to alteration or initiation of medical or surgical therapy to improve outcomes in others. Thus, institution of 2-day WGS at time of acute presentation opens the possibility of early implementation of precision medicine. This implementation may create opportunities for early interventional therapies, which would frequently be novel or off-label, that may alter disease trajectory in infants with what would otherwise be fatal disease. Widespread deployment of rapid WGS and precision medicine will raise ethical issues pertaining to interpretation of variants of unknown significance, discovery of incidental findings related to adult onset conditions and carrier status, and implementation of medical therapies for which little is known in terms of risks and benefits. Despite these challenges, precision neonatology has significant potential both to decrease infant mortality related to genetic diseases with onset in newborns and to facilitate parental decision-making regarding transition to palliative care.