Watson Sonya, Ngo Kathie J, Stevens Hannah A, Wong Darice Y, Kim Jihye, Song Yongjun, Han Beomman, Hyun Seong-In, Khang Rin, Ryu Seung Woo, Lee Eugene, Seo Gohun, Lee Hane, Lajonchere Clara, Fogel Brent L
From the Department of Neurology (S.W., K.J.N., H.A.S., D.Y.W., C.L., B.L.F.), the Clinical Neurogenomics Research Center (S.W., H.A.S., D.Y.W., C.L., B.L.F.), the Institute for Precision Health (S.W., C.L., B.L.F.), and the Department of Human Genetics (S.W., B.L.F.), David Geffen School of Medicine, University of California at Los Angeles (UCLA); 3billion, Inc. (J.K., Y.S., B.H., S.-I.H., R.K., S.W.R., E.L., G.S., H.L.).
Neurol Genet. 2024 Apr 9;10(3):e200133. doi: 10.1212/NXG.0000000000200133. eCollection 2024 Jun.
Exome sequencing (ES) demonstrates a 20-50 percent diagnostic yield for patients with a suspected monogenic neurologic disease. Despite the proven efficacy in achieving a diagnosis for such patients, multiple barriers for obtaining exome sequencing remain. This study set out to assess the efficacy of ES in patients with primary neurologic phenotypes who were appropriate candidates for testing but had been unable to pursue clinical testing.
A total of 297 patients were identified from the UCLA Clinical Neurogenomics Research Center Biobank, and ES was performed, including bioinformatic assessment of copy number variation and repeat expansions. Information regarding demographics, clinical indication for ES, and reason for not pursuing ES clinically were recorded. To assess diagnostic efficacy, variants were interpreted by a multidisciplinary team of clinicians, bioinformaticians, and genetic counselors in accordance with the American College of Medical Genetics and Genomics variant classification guidelines. We next examined the specific barriers to testing for these patients, including how frequently insurance-related barriers such as coverage denials and inadequate coverage of cost were obstacles to pursuing exome sequencing.
The cohort primarily consisted of patients with sporadic conditions (n = 126, 42.4%) of adult-onset (n = 239, 80.5%). Cerebellar ataxia (n = 225, 75.8%) was the most common presenting neurologic phenotype. Our study found that in this population of mostly adult patients with primary neurologic phenotypes that were unable to pursue exome sequencing clinically, 47 (15.8%) had diagnostic results while an additional 24 patients (8.1%) had uncertain results. Of the 297 patients, 206 were initially recommended for clinical exome but 88 (42.7%) could not pursue ES because of insurance barriers, of whom 14 (15.9%) had diagnostic findings, representing 29.8% of all patients with diagnostic findings. In addition, the incorporation of bioinformatic repeat expansion testing was valuable, identifying a total of 8 pathogenic repeat expansions (17.0% of all diagnostic findings) including 3 of the common spinocerebellar ataxias and 2 patients with Huntington disease.
These findings underscore the importance and value of clinical ES as a diagnostic tool for neurogenetic disease and highlight key barriers that prevent patients from receiving important clinical information with potential treatment and psychosocial implications for patients and family members.
外显子组测序（ES）对疑似单基因神经疾病患者的诊断率为20%-50%。尽管已证实其在为这类患者实现诊断方面的有效性，但获取外显子组测序仍存在多重障碍。本研究旨在评估ES在患有原发性神经表型且适合检测但此前无法进行临床检测的患者中的有效性。
从加州大学洛杉矶分校临床神经基因组学研究中心生物样本库中识别出297例患者，并进行了外显子组测序，包括对拷贝数变异和重复序列扩增的生物信息学评估。记录了有关人口统计学、外显子组测序的临床指征以及未进行临床外显子组测序的原因等信息。为评估诊断有效性，由临床医生、生物信息学家和遗传咨询师组成的多学科团队根据美国医学遗传学与基因组学学会的变异分类指南对变异进行了解读。接下来，我们研究了这些患者进行检测的具体障碍，包括保险相关障碍（如保险拒绝承保和费用覆盖不足）阻碍外显子组测序的频率。
该队列主要由成年起病的散发性疾病患者（n = 126，42.4%）组成，其中成年患者有239例（80.5%）。小脑共济失调（n = 225，75.8%）是最常见的神经表型。我们的研究发现，在这群大多为成年且患有原发性神经表型但无法进行临床外显子组测序的患者中，47例（15.8%）有诊断结果，另有24例患者（8.1%）结果不确定。在这297例患者中，206例最初被推荐进行临床外显子组测序，但88例（42.7%）因保险障碍无法进行外显子组测序，其中14例（15.9%）有诊断结果，占所有有诊断结果患者的29.8%。此外，纳入生物信息学重复序列扩增检测很有价值，共识别出8个致病性重复序列扩增（占所有诊断结果的17.0%），包括3例常见的脊髓小脑共济失调和2例亨廷顿病患者。
这些发现强调了临床外显子组测序作为神经遗传疾病诊断工具的重要性和价值，并突出了阻碍患者获得具有潜在治疗意义及对患者和家属有心理社会影响的重要临床信息的关键障碍。
