Sanquin Blood Cell Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Pediatric Hematology Clinic and the Laboratory for Leukocyte Function, Meir Medical Center, Kfar Saba, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
J Med Genet. 2018 Mar;55(3):166-172. doi: 10.1136/jmedgenet-2017-105022. Epub 2018 Jan 13.
Mutations in the gene that encodes p47, a subunit of the NADPH oxidase complex, cause chronic granulomatous disease (CGD). In Kavkazi Jews, a c.579G>A (p.Trp193Ter) mutation in is frequently found, leading to CGD. The same mutation is found in about 1% of Ashkenazi Jews, although Ashkenazi CGD patients with this mutation have never been described.
We used Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), gene scan analysis and Ion Torrent Next Generation Sequencing for genetic analysis, and measured NADPH oxidase activity and p47 expression.
In an Ashkenazi couple expecting a baby, both parents were found to be heterozygotes for this mutation, as was the fetus. However, segregation analysis in the extended family was consistent with the fetus inheriting both carrier alleles from the parents. MLPA indicated four complete genes in the fetus and three in each parent. Gene sequencing confirmed these results. Analysis of fetal leucocytes obtained by cordocentesis revealed substantial oxidase activity with three different assays, which was confirmed after birth. In six additional Ashkenazi carriers of the c.579G>A mutation, we found five individuals with three complete genes of which one was mutated (like the parents), and one individual with in addition a fusion gene of with a pseudogene.
These results point to the existence of a 'false-carrier' state in Ashkenazi Jews and have wide implications regarding pre-pregnancy screening in this and other population groups.
编码 NADPH 氧化酶复合物亚单位 p47 的 基因突变可导致慢性肉芽肿病（CGD）。在卡瓦卡兹犹太人中，经常发现 基因中的 c.579G>A（p.Trp193Ter）突变，导致 CGD。同样的突变在约 1%的阿什肯纳兹犹太人中发现，尽管具有这种突变的阿什肯纳兹 CGD 患者从未被描述过。
我们使用 Sanger 测序、多重连接依赖性探针扩增（MLPA）、基因扫描分析和 Ion Torrent 下一代测序进行基因分析，并测量 NADPH 氧化酶活性和 p47 表达。
在一对期待婴儿的阿什肯纳兹夫妇中，父母双方均为该突变的杂合子，胎儿也是如此。然而，对扩展家族的分离分析表明，胎儿从父母双方继承了两个携带突变的等位基因。MLPA 表明胎儿中有四个完整的 基因，而父母双方各有三个。基因测序证实了这些结果。通过脐带穿刺术获得的胎儿白细胞分析显示，三种不同的检测方法均具有大量的氧化酶活性，出生后得到了证实。在另外 6 名携带 基因 c.579G>A 突变的阿什肯纳兹携带者中，我们发现 5 人有三个完整的 基因，其中一个发生了突变（与父母相同），1 人除了有一个与假基因融合的 基因。
这些结果表明阿什肯纳兹犹太人中存在“假携带者”状态，这对该人群和其他人群的孕前筛查具有广泛的影响。
