Clinical and molecular phenotype of Aicardi-Goutieres syndrome
Clinical and molecular phenotype of Aicardi-Goutieres syndrome
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DOI：
10.1086/521373
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发表时间：
2007-10-01
影响因子：
9.8
通讯作者：
Crow, Yanick J.
中科院分区：
文献类型：
--
作者：
Rice, Gillian;Patrick, Teresa;Crow, Yanick J.
Aicardi-Goutieres综合征（AGS）是一种遗传性脑病，其临床特征与宫内获得性病毒感染相似。AGS表现出基因座异质性，在编码3 '-> 5'核酸外切酶TREX 1和RNASEH 2核酸内切酶复合物的三个亚基的基因中鉴定出突变。为了确定AGS的分子谱，我们对来自127个家系的临床诊断为该疾病的患者进行了突变筛查。在31、3、47和18个家族中分别观察到TREX 1、RNASEH 2A、RNASEH 2B和RNASEH 2C的双等位基因突变。在5个家族中，我们仅在一个等位基因上发现了RNASEH 2A或RNASEH 2B突变。在一名儿童中，该疾病是由于TREX 1新发杂合突变而发生的。在22个家族中，没有发现突变。TREX 1的错义突变是常见的，尽管在北方欧洲的患者中经常观察到特定的错义突变。RNASEH 2A、RNASEH 2B和RNASEH 2C中几乎所有的突变都是错义的。我们在13个巴基斯坦家庭中发现了RNASEH 2C创始人突变。我们还收集了123例突变阳性患者的临床数据。可以描述两种临床表现：早发性新生儿形式，特别是TREX 1突变引起的先天性感染，以及迟发性表现，有时发生在正常发育数月后，偶尔与神经功能显著保留相关，最常见的是由于RNASEH 2B突变。死亡率与基因型相关; 34.3%的TREX 1、RNASEH 2A和RNASEH 2C突变患者与8.0%的RNASEH 2B突变阳性患者已知已经死亡（P = 0.001）。我们的分析定义了AGS的表型谱，并提出了在这种异质性疾病中的一致突变筛查策略。此外，我们的数据表明，至少还有一个引起AGS的基因有待鉴定.
Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-> 5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later- onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P = .001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation- screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS- causing gene remains to be identified.