Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy
Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy
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DOI：
10.1212/nxg.0000000000000305
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发表时间：
2019-02-01
影响因子：
3.1
通讯作者：
Padiath, Quasar S.
中科院分区：
文献类型：
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作者：
Nmezi, Bruce;Giorgio, Elisa;Padiath, Quasar S.
目的对LMNB1上游基因缺失患者进行临床、放射学和分子分析。方法对不同临床中心的患者进行详细的神经学检查、MRI检查、定制阵列比较基因组杂交（aCGH）分析和表达分析。所有程序均由各院校的院校检讨委员会核准。结果5例患者来自3个独立家庭，年龄32 ~ 52岁，神经系统症状包括进行性声音减退、上肢和下肢无力、痉挛、小脑功能障碍，mri表现为广泛的白质改变。患者在LMNB1上游有独特的非复发性缺失，大小从250 kb到670 kb不等。删除连接嵌入在重复元件中。表达分析显示患者细胞中LMNB1表达增加。我们的研究结果证实了LMNB1上游缺失与先前在单个家族中报道的白质营养不良之间的关联，扩展了这种情况的表型和分子描述。尽管由于LMNB1重复，临床和影像学特征与常染色体显性白质营养不良重叠，但LMNB1上游缺失的患者在症状发作时年龄更早，缺乏早期自主神经异常，并且在MRI上表现为小脑受损伤较小，脊髓直径较小。aCGH分析定义了致病所需的一个较小的最小临界区域，并揭示了重复DNA基因组元件的缺失。寻找LMNB1结构变异（重复和上游缺失）应该是常染色体显性成人发病白质营养不良患者调查的一个组成部分。
Objective Clinical, radiologic, and molecular analysis of patients with genomic deletions upstream of the LMNB1 gene. Methods Detailed neurologic, MRI examinations, custom array comparative genomic hybridization (aCGH) analysis, and expression analysis were performed in patients at different clinical centers. All procedures were approved by institutional review boards of the respective institutions. Results Five patients from 3 independent families presented at ages ranging from 32 to 52 years with neurologic symptoms that included progressive hypophonia, upper and lower limb weakness and spasticity, and cerebellar dysfunction and MRIs characterized by widespread white matter alterations. Patients had unique nonrecurrent deletions upstream of the LMNB1, varying in size from 250 kb to 670 kb. Deletion junctions were embedded in repetitive elements. Expression analysis revealed increased LMNB1 expression in patient cells. Conclusions Our findings confirmed the association between LMNB1 upstream deletions and leukodystrophy previously reported in a single family, expanding the phenotypic and molecular description of this condition. Although clinical and radiologic features overlapped with those of autosomal dominant leukodystrophy because of LMNB1 duplications, patients with deletions upstream of LMNB1 had an earlier age at symptom onset, lacked early dysautonomia, and appeared to have lesser involvement of the cerebellum and sparing of the spinal cord diameter on MRI. aCGH analysis defined a smaller minimal critical region required for disease causation and revealed that deletions occur at repetitive DNA genomic elements. Search for LMNB1 structural variants (duplications and upstream deletions) should be an integral part of the investigation of patients with autosomal dominant adult-onset leukodystrophy.