Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing

IF 4.3 4区 医学 Q1 OBSTETRICS & GYNECOLOGY Obstetrical & Gynecological Survey Pub Date : 2023-08-01 DOI:10.1097/01.ogx.0000967016.12085.9e
Mallory J. Owen, Meredith S. Wright, Sergey Batalov, Yonghyun Kwon, Yan Ding, Kevin K. Chau, Shimul Chowdhury, Nathaly M. Sweeney, Elizabeth Kiernan, Andrew Richardson, Emily Batton, Rebecca J. Baer, Gretchen Bandoli, Joseph G. Gleeson, Matthew Bainbridge, Christina D. Chambers, Stephen F. Kingsmore
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Abstract

ABSTRACT Infant mortality rates are quite high even in developed countries; in the United States, infant deaths occur approximately 1 in 200 live births. The leading cause of infant mortality is congenital malformation or chromosomal abnormality, which cause roughly 20% of infant deaths, followed by other causes such as pregnancy complications, preterm birth or low birth weight, and sudden infant death syndrome. Improvements in treatments for certain conditions such as pregnancy complications or prematurity have previously resulted in a reduction in mortality due to these causes. Although the same may be true of congenital malformations or chromosomal abnormalities, the relationship between these factors and infant mortality has not been closely examined. Previous studies have largely been retrospective in nature and varied greatly among method and records used, perpetuating inaccuracies and imprecision. This study aimed to clarify and add to previous literature by examining the relationship between single-locus genetic disease (Mendelian genetic disease) and overall infant mortality. This study applied diagnostic whole-genome sequencing (WGS) to infants in intensive care to diagnose diseases of unknown etiology in a single hospital system between 2015 and 2020. The study was retrospective and included review of medical records and death certificates, as well as results from WGS. Where possible, WGS information was obtained on living infants and their parents, and where that was not possible, it was obtained postmortem. Death certificates and causes of death were also examined and compared with WGS results. In the final sample, 112 infants who died underwent WGS either premortem or postmortem. WGS identified genetic diseases in 46 (41%) of these infants. Of the genetic diseases identified, 83% had previous evidence supporting an association with childhood mortality, and evidence was gathered from previous literature that could improve outcomes for 30%. Death certificate comparisons showed that of 45 infants where WGS showed underlying genetic disease, 62% were not reported on the certificate or attributed to the cause of death. In addition to the 112 infants who died, the study population included 434 infants who survived and also had WGS performed. No significant differences were found between the groups in sex, race, or ethnicity. Types of genetic disease varied between infants who died and those who survived, with only 4% being found in both. Certain diseases were more likely to occur in infants who survived, and others were more likely to occur in infants who died. Specific etiology had some prognostic value, positively predicting either death or survival. These results indicate that first, after examination of WGS in comparison with death certificates, genetic diseases are chronically underreported. In addition, WGS showed that etiology of leading causes of infant mortality could be fundamentally different than previously thought. WGS is also not currently a widespread treatment, and although steps are being taken to make it more widely accessible, there are still many changes that need to be made. This study is limited by its small size, and may have limited generalizability to other patient populations. Future research should characterize the optimal breadth of WGS testing and implementation, as well as the potential for WGS to reduce infant mortality by identifying treatable disorders.
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用全基因组测序重新分类婴儿死亡的病因
即使在发达国家,婴儿死亡率也相当高;在美国,每200个活产婴儿中就有1个死亡。婴儿死亡的主要原因是先天性畸形或染色体异常,约占婴儿死亡的20%,其次是其他原因,如妊娠并发症、早产或出生体重过低,以及婴儿猝死综合症。对某些疾病,如妊娠并发症或早产的治疗方法的改进,以前曾导致这些原因造成的死亡率下降。虽然先天性畸形或染色体异常可能也是如此,但这些因素与婴儿死亡率之间的关系尚未得到仔细研究。以前的研究在很大程度上是回顾性的,在使用的方法和记录之间差异很大,使不准确性和不精确性永久化。本研究旨在通过检查单位点遗传病(孟德尔遗传病)与总体婴儿死亡率之间的关系来澄清和补充先前的文献。本研究将诊断性全基因组测序(WGS)应用于2015年至2020年单一医院系统重症监护婴儿诊断病因不明的疾病。这项研究是回顾性的,包括对医疗记录和死亡证明的审查,以及WGS的结果。在可能的情况下,获取在世婴儿及其父母的WGS信息,如果不可能,则在死后获得。还检查了死亡证明和死亡原因,并与WGS结果进行了比较。在最后的样本中,112名死亡的婴儿在死前或死后进行了WGS。WGS在这些婴儿中发现了46例(41%)遗传疾病。在已确定的遗传疾病中,有83%的人先前有证据支持与儿童死亡率有关,并且从先前的文献中收集的证据可以改善30%的结果。死亡证明比较显示,在45名WGS显示潜在遗传疾病的婴儿中,62%没有在证明上报告或归因于死亡原因。除了死亡的112名婴儿外,研究人群还包括434名幸存的婴儿,他们也进行了WGS。在性别、种族或民族方面,各组之间没有发现显著差异。在死亡和存活的婴儿中,遗传疾病的类型各不相同,两者中只有4%被发现。某些疾病更可能发生在存活下来的婴儿身上,而另一些疾病更可能发生在死亡的婴儿身上。特定病因有一定的预后价值,对死亡或生存有积极的预测作用。这些结果表明,首先,在将WGS与死亡证明进行比较后,遗传疾病的报告长期偏低。此外,WGS表明,婴儿死亡的主要原因的病因学可能与以前认为的根本不同。WGS目前也不是一种广泛的治疗方法,尽管正在采取措施使其更广泛地可获得,但仍有许多需要做出的改变。这项研究的局限性在于其规模小,并且可能对其他患者群体的推广作用有限。未来的研究应该确定WGS测试和实施的最佳广度,以及WGS通过识别可治疗的疾病来降低婴儿死亡率的潜力。
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来源期刊
CiteScore
2.70
自引率
3.20%
发文量
245
审稿时长
>12 weeks
期刊介绍: ​Each monthly issue of Obstetrical & Gynecological Survey presents summaries of the most timely and clinically relevant research being published worldwide. These concise, easy-to-read summaries provide expert insight into how to apply the latest research to patient care. The accompanying editorial commentary puts the studies into perspective and supplies authoritative guidance. The result is a valuable, time-saving resource for busy clinicians.
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