Whole exome sequencing in neurogenetic odysseys: An effective, cost- and time-saving diagnostic approach

Background
Diagnostic trajectories for neurogenetic disorders frequently require the use of considerable time and resources, exposing patients and families to so-called “diagnostic odysseys”. Previous studies have provided strong evidence for increased diagnostic and clinical utility of whole-exome sequencing in medical genetics. However, specific reports assessing its utility in a setting such as ours- a neurogeneticist led academic group serving in a low-income country—are rare.
Objectives
To assess the diagnostic yield of WES in patients suspected of having a neurogenetic condition and explore the cost-effectiveness of its implementation in a research group located in an Argentinean public hospital.
Methods
This is a prospective study of the clinical utility of WES in a series of 40 consecutive patients selected from a Neurogenetic Clinic of a tertiary Hospital in Argentina. We evaluated patients retrospectively for previous diagnostic trajectories. Diagnostic yield, clinical impact on management and economic diagnostic burden were evaluated.
Results
We demonstrated the clinical utility of Whole Exome Sequencing in our patient cohort, obtaining a diagnostic yield of 40% (95% CI, 24.8%-55.2%) among a diverse group of neurological disorders. The average age at the time of WES was 23 (range 3–70). The mean time elapsed from symptom onset to WES was 11 years (range 3–42). The mean cost of the diagnostic workup prior to WES was USD 1646 (USD 1439 to 1853), which is 60% higher than WES cost in our center.
Conclusions
WES for neurogenetics proved to be an effective, cost- and time-saving approach for the molecular diagnosis of this heterogeneous and complex group of patients.

研究背景
神经遗传性疾病的诊断路径往往需要耗费大量时间与资源，令患者及其家庭陷入所谓的“诊断漫游（diagnostic odysseys）”。既往研究已提供了强有力的证据，证实全外显子组测序（whole-exome sequencing, WES）在医学遗传学领域可提升诊断效能与临床实用性。然而，针对低收入国家场景下、由神经遗传学家主导的学术医疗团队开展的相关实用性评估报告仍较为罕见。

研究目的
评估疑似罹患神经遗传性疾病的患者接受全外显子组测序的诊断检出率，并探索该技术在阿根廷某公立医院科研团队中应用的成本效益。

研究方法
本研究为前瞻性研究，纳入阿根廷某三级医院神经遗传门诊连续收治的40例疑似神经遗传性疾病患者。我们对患者既往的诊断轨迹进行回顾性分析，评估了WES的诊断检出率、对临床诊疗管理的影响以及诊断相关的经济负担。

研究结果
本研究队列证实了WES的临床实用价值：在涵盖多种神经系统疾病的异质性患者群体中，其诊断检出率达40%（95%置信区间：24.8%~55.2%）。患者接受WES时的平均年龄为23岁（年龄范围：3~70岁）；从症状发作至接受WES的平均间隔时长为11年（范围：3~42年）。WES开展前的诊断检查平均花费为1646美元（区间：1439~1853美元），较本中心WES的检测成本高出60%。

研究结论
针对神经遗传性疾病患者，WES是一种高效、经济且省时的分子诊断手段，可有效应对这类异质性强、病情复杂的患者群体的诊断需求。