Universal Exome Sequencing in Critically Ill Adults: A Diagnostic Yield of 25% and Race-Based Disparities in Access to Genetic Testing.
Universal Exome Sequencing in Critically Ill Adults: A Diagnostic Yield of 25% and Race-Based Disparities in Access to Genetic Testing.
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通用%20外显子组%20测序%20in%20严重%20Ill%20成人：%20A%20诊断%20产量%20%2025%%20和%20基于种族的%20差异%20in%20访问%20至%20遗传%20测试。
DOI：
10.1101/2024.03.11.24304088
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Drivas,TheodoreG
中科院分区：
文献类型：
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作者：
Gold,Jessica;Kripke,ColleenM;RegeneronGeneticsCenter;PennMedicineBioBank;Drivas,TheodoreG
许多研究都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，在危重成人中进行的等效调查仍然明显缺席。我们回顾性分析了宾夕法尼亚医学生物银行（PMBB）提供的全外显子组测序（WES）数据，这些数据来自365名年龄在18-40岁、宾夕法尼亚大学卫生系统重症监护病房（ICU）住院的符合我们研究纳入标准的年轻成人患者。对于每个参与者，两名医学遗传学和内科培训的临床医生审查WES报告和患者图表，以进行变异分类、结果解释和鉴定与其危重疾病相关的遗传诊断。在我们研究的365个个体中，发现90个（24.7%）在WES上有明确的诊断结果；另外40例（11.0%）发现了不确定意义的可疑变异（VUS）；另外16个（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不随患者年龄的增加而降低。受影响的基因主要与心脏功能（18.8%）、血管健康（16.7%）、癌症（16.7%）和肺部疾病（11.5%）有关。在ICU入院时，只有一半的诊断结果是已知的，并记录在患者图表中。在ehr报告的种族亚组分析中出现了显著差异，在ICU入院时，63.5%的白人患者已知/记录的遗传诊断，而只有28.6%的黑人或西班牙裔患者。有一种趋势是，无证遗传诊断的患者死亡率增加66%，这使得这些基于种族的遗传诊断差异更加令人担忧。总的来说，在icu住院的成年患者中，11.2%的患者发现通用外显子组测序产生了新的明确诊断。在这些诊断中，76.6%给出了具体的改变护理的医疗管理建议。我们的研究表明，外显子组测序在危重年轻人中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著的种族差异表明，对危重成人进行广泛和普遍的基因检测方法是必要的。在成年人口中广泛实施全面的基因测序有望加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距，最终促进更公平的医疗保健服务。
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.