Genetic heterogeneity in 26 infants with a hypomyelinating leukodystrophy
Genetic heterogeneity in 26 infants with a hypomyelinating leukodystrophy
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DOI：
10.1007/s00439-015-1617-7
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发表时间：
2016-01-01
期刊：
影响因子：
5.3
通讯作者：
Kure, Shigeo
中科院分区：
文献类型：
--
作者：
Arai-Ichinoi, Natsuko;Uematsu, Mitsugu;Kure, Shigeo
通过磁共振成像（MRI）检测到的T2高信号脑白色病变是异质性疾病组的特征。持续的T2高信号结合T1等或高信号的白色物质提示缺乏正常的髓鞘形成，即髓鞘形成不足。然而，仅根据MRI结果精确诊断低髓鞘化脑白质营养不良可能是困难的，特别是在疾病的早期阶段。我们研究了26例根据MRI结果和临床特征诊断为低髓鞘化脑白质营养不良的患者，通过染色体分析、靶基因分析和阵列比较基因组杂交（aCGH）分析来揭示其遗传病因。然后，对于17例传统分析无法解释的髓鞘形成不足的患者，进行全外显子组测序（WES）。在58%的入组患者（15/26）中确认了推定诊断，涉及9种不同的遗传背景。最常见的背景是18 q缺失综合征和Pelizaeus-Merzbacher病，两者的发病率均为12%（3/26）。染色体分析、靶基因分析和aCGH的诊断率为31%（8/26），1例患者临床诊断为Cockayne综合征。使用WES，在6个个体（35%，6/17）中鉴定出以下髓鞘形成不足的致病基因：TUBB 4A、POLR 3B、KCNT 1和MCOLN 1，并且这些基因中的一些不仅是髓鞘形成不足的致病基因，而且是髓鞘形成障碍或延迟髓鞘形成的致病基因。我们的研究结果提示持续性白色病变患者存在异质性遗传背景。这些数据也表明，WES可能是一个快速和有用的工具，用于确定潜在的遗传原因未确诊的脑白质营养不良。
T2 hyperintensity of brain white matter lesions detected by magnetic resonance imaging (MRI) are characteristic of a heterogeneous group of diseases. Persistent T2 high intensity in combination with T1 iso- or high intensity of white matter in infants indicates a lack of normal myelination, that is, hypomyelination. However, the precise diagnosis of hypomyelinating leukodystrophy based solely on MRI findings can be difficult, especially in the early stage of the disease. We studied 26 patients who were diagnosed with hypomyelinating leukodystrophy according to MRI findings and clinical features to uncover their genetic etiology through chromosomal analyses, targeted gene analyses, and an array comparative genomic hybridization (aCGH) assay. Then, for the 17 patients with unexplained hypomyelination by traditional analyses, whole-exome sequencing (WES) was performed. The presumptive diagnoses were confirmed in 58 % of the enrolled patients (15/26) and involved 9 different genetic backgrounds. The most frequent backgrounds were 18q deletion syndrome and Pelizaeus-Merzbacher disease, with an incidence of 12 % (3/26) for both. The diagnostic rate of chromosomal analyses, targeted gene analyses, and aCGH was 31 % (8/26), and one patient was clinically diagnosed with Cockayne syndrome. Using WES, the following causative genes of hypomyelination were identified in six individuals (35 %, 6/17): TUBB4A, POLR3B, KCNT1, and MCOLN1, and some of those genes were pathogenic for not only hypomyelination but also dysmyelination or delayed myelination. Our findings suggested heterogeneous genetic backgrounds in patients with persistent white matter lesions. These data also indicate that WES may be a rapid and useful tool for identifying the underlying genetic causes of undiagnosed leukodystrophies.