Gold Jessica, Kripke Colleen M, Drivas Theodore G
Division of Clinical Genetics, Department of Pediatrics, Northwell Health, Great Neck, NY 11021, USA.
Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19194, USA.
medRxiv. 2024 Apr 1:2024.03.11.24304088. doi: 10.1101/2024.03.11.24304088.
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.
众多研究强调了外显子组或基因组测序在危重症儿科人群中的诊断和治疗潜力。然而，针对危重症成人的同等研究却明显缺失。我们回顾性分析了宾夕法尼亚大学医疗系统中所有365名年龄在18至40岁之间、入住重症监护病房（ICU）且符合我们研究纳入标准的年轻成年患者通过宾夕法尼亚医学生物样本库（PMBB）获取的全外显子组测序（WES）数据。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查阅了WES报告和患者病历，以进行变异分类、结果解读，并识别与其危重症相关的基因诊断。在我们研究的365名个体中，90名（24.7%）在WES上有明确的诊断结果；另外40名（11.0%）发现有意义不确定的可疑变异（VUS）；还有16名（4.4%）有医学上可采取行动的偶然发现。外显子组测序的诊断率并未随患者年龄增加而降低。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ICU入院时，所有诊断结果中只有一半在患者病历中有记录。按电子健康记录（EHR）报告的种族进行亚组分析时出现了显著差异，ICU入院时，63.5%的白人患者的基因诊断有记录，而黑人或西班牙裔患者只有28.6%有记录。基因诊断未记录的患者死亡率有增加66%的趋势，这使得基于种族的基因诊断差异更令人担忧。总体而言，在入住ICU的成年患者中进行普遍的外显子组测序发现，11.2%的患者有新的明确诊断。在这些诊断中，76.6%给出了改变治疗方案的具体医疗管理建议。我们的研究表明，外显子组测序在危重症年轻成年人中的诊断效用与在新生儿和儿科人群中观察到的相似，且与年龄无关。我们在基因诊断中发现的高诊断率和显著的基于种族差异表明，对于危重症成年人应采用广泛且普遍的基因检测方法。在成年人群中广泛实施全面的基因测序有望改善所有人的医疗护理，并有可能纠正基因检测转诊中的差异，最终促进更公平的医疗服务提供。
