High Diagnostic Utility Incorporating a Targeted Neurodegeneration Gene Panel With MRI Brain Diagnostic Algorithms in Patients With Young-Onset Cognitive Impairment With Leukodystrophy.
High Diagnostic Utility Incorporating a Targeted Neurodegeneration Gene Panel With MRI Brain Diagnostic Algorithms in Patients With Young-Onset Cognitive Impairment With Leukodystrophy.
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DOI：
10.3389/fneur.2021.631407
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发表时间：
2021
影响因子：
3.4
通讯作者：
Ng ASL
中科院分区：
文献类型：
--
作者：
Chen Z;Tan YJ;Lian MM;Tandiono M;Foo JN;Lim WK;Kandiah N;Tan EK;Ng ASL
脑白质营养不良症是一组不同的遗传性疾病，选择性地涉及大脑白质，是年轻发病认知障碍的常见原因。基因诊断具有挑战性。将脑磁共振成像（MRI）诊断算法与新一代测序（NGS）结合起来用于实际临床诊断的数据有限。我们使用定制设计的200个神经变性相关基因对45例年轻发病认知障碍伴脑白质营养不良患者进行测序，并根据van der Knaap等人的MRI诊断算法对其进行分类。我们发现20/45（44.4%）的患者携带致病变异或预测为致病的新变异（1例在CSF1R， 2例在HTRA1, 17例在NOTCH3）。所有确定遗传诊断的患者都有与特定遗传条件一致的MRI脑模式。超过一半（19/37,51.4%）MRI改变符合小血管病变继发性血管性认知障碍（VCI-SVD）的患者存在致病性变异，包括所有具有致病性NOTCH3（17/19, 89.5%）和HTRA1变异（2/19,11.5%）的患者。在携带致病性NOTCH3变异的患者中，13/17（76.5%）携带主要见于东亚的p.R544C变异。前颞白质受损伤仅见于致病NOTCH3变异患者（6/17,35.3%）。总的来说，我们证明了在年轻发病的脑白质营养不良的认知障碍患者中，结合靶向神经变性基因面板和基于mri的诊断算法具有很高的诊断效用。
Leukodystrophies are a diverse group of genetic disorders that selectively involve the white matter of the brain and are a frequent cause of young-onset cognitive impairment. Genetic diagnosis is challenging. Data on the utility of incorporating brain magnetic resonance imaging (MRI) diagnostic algorithms with next-generation sequencing (NGS) for diagnosis in a real-life clinical setting is limited. We performed sequencing using a custom-designed panel of 200 neurodegeneration-associated genes on 45 patients with young-onset cognitive impairment with leukodystrophy, and classified them based on van der Knaap et al.'s MRI diagnostic algorithm. We found that 20/45 (44.4%) patients carried pathogenic variants or novel variants predicted to be pathogenic (one in CSF1R, two in HTRA1 and 17 in NOTCH3). All patients with an established genetic diagnosis had an MRI brain pattern consistent with a specific genetic condition/s. More than half (19/37, 51.4%) of patients with MRI changes consistent with vascular cognitive impairment secondary to small vessel disease (VCI-SVD) had pathogenic variants, including all patients with pathogenic NOTCH3 (17/19, 89.5%) and HTRA1 variants (2/19, 11.5%). Amongst patients harboring pathogenic NOTCH3 variants, 13/17 (76.5%) carried the p.R544C variant seen predominantly in East Asians. Anterior temporal white matter involvement was seen only in patients with pathogenic NOTCH3 variants (6/17, 35.3%). Overall, we demonstrated a high diagnostic utility incorporating a targeted neurodegeneration gene panel and MRI-based diagnostic algorithms in young-onset cognitive impairment patients with leukodystrophy.
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