Numerous studies have underscored the diagnostic and therapeutic potential of exome or genome sequencing in critically ill pediatric populations. However, an equivalent investigation in critically ill adults remains conspicuously absent. We retrospectively analyzed whole exome sequencing (WES) data available through the PennMedicine Biobank (PMBB) from all 365 young adult patients, aged 18-40 years, with intensive care unit (ICU) admissions at the University of Pennsylvania Health System who met inclusion criteria for our study. For each participant, two Medical Genetics and Internal Medicine-trained clinicians reviewed WES reports and patient charts for variant classification, result interpretation, and identification of genetic diagnoses related to their critical illness. Of the 365 individuals in our study, 90 (24.7%) were found to have clearly diagnostic results on WES; an additional 40 (11.0%) had a suspicious variant of uncertain significance (VUS) identified; and an additional 16 (4.4%) had a medically actionable incidental finding. The diagnostic rate of exome sequencing did not decrease with increasing patient age. Affected genes were primarily involved in cardiac function (18.8%), vascular health (16.7%), cancer (16.7%), and pulmonary disease (11.5%). Only half of all diagnostic findings were known and documented in the patient chart at the time of ICU admission. Significant disparities emerged in subgroup analysis by EHR-reported race, with genetic diagnoses known/documented for 63.5% of White patients at the time of ICU admission but only for 28.6% of Black or Hispanic patients. There was a trend towards patients with undocumented genetic diagnoses having a 66% increased mortality rate, making these race-based disparities in genetic diagnosis even more concerning. Altogether, universal exome sequencing in ICU-admitted adult patients was found to yield a new definitive diagnosis in 11.2% of patients. Of these diagnoses, 76.6% conferred specific care-altering medical management recommendations. Our study suggests that the diagnostic utility of exome sequencing in critically ill young adults is similar to that observed in neonatal and pediatric populations and is age-independent. The high diagnostic rate and striking race-based disparities we find in genetic diagnoses argue for broad and universal approaches to genetic testing for critically ill adults. The widespread implementation of comprehensive genetic sequencing in the adult population promises to enhance medical care for all individuals and holds the potential to rectify disparities in genetic testing referrals, ultimately promoting more equitable healthcare delivery.

中文翻译：

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危重成人的通用外显子组测序：诊断率达 25%，且基因检测机会存在种族差异

许多研究强调了外显子组或基因组测序在危重儿科人群中的诊断和治疗潜力。然而，对危重成人的类似调查仍然明显缺乏。我们回顾性分析了通过 PennMedicine Biobank (PMBB) 获得的所有 365 名年轻成年患者的全外显子测序 (WES) 数据，这些患者年龄为 18-40 岁，入住宾夕法尼亚大学卫生系统重症监护室 (ICU)，且符合纳入标准为了我们的学习。对于每位参与者，两名接受过医学遗传学和内科培训的临床医生审查了 WES 报告和患者图表，以进行变异分类、结果解释以及与其危重疾病相关的遗传诊断的识别。在我们研究的 365 人中，90 人（24.7%）被发现有明确的 WES 诊断结果；另外 40 例 (11.0%) 发现了意义不确定的可疑变异 (VUS)；另外 16 人（4.4%）有可采取医疗行动的偶然发现。外显子组测序的诊断率并没有随着患者年龄的增加而降低。受影响的基因主要涉及心脏功能（18.8%）、血管健康（16.7%）、癌症（16.7%）和肺部疾病（11.5%）。在入住 ICU 时，只有一半的诊断结果已知并记录在患者病历中。EHR 报告的种族亚组分析中出现了显着差异，入住 ICU 时 63.5% 的白人患者已知/记录有基因诊断，但只有 28.6% 的黑人或西班牙裔患者已知/记录有基因诊断。有一种趋势是，未经记录的基因诊断患者的死亡率增加了 66%，这使得基因诊断中基于种族的差异更加令人担忧。总的来说，对 ICU 入住的成年患者进行通用外显子组测序，对 11.2% 的患者进行了新的明确诊断。在这些诊断中，76.6% 提出了具体的改变护理的医疗管理建议。我们的研究表明，外显子组测序对危重年轻人的诊断效用与在新生儿和儿科人群中观察到的相似，并且与年龄无关。我们在基因诊断中发现的高诊断率和显着的基于种族的差异表明需要对危重成人进行广泛且普遍的基因检测方法。在成年人群中广泛实施全面基因测序有望增强所有人的医疗保健，并有可能纠正基因检测转诊方面的差异，最终促进更公平的医疗服务。