RT Journal Article
SR Electronic
T1 A false-carrier state for the c.579G>A mutation in the NCF1 gene in Ashkenazi Jews
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 166
OP 172
DO 10.1136/jmedgenet-2017-105022
VO 55
IS 3
A1 Martin De Boer
A1 Ronit Gavrieli
A1 Karin van Leeuwen
A1 Haike Reznik Wolf
A1 Maya Dushnitzki
A1 Yifaat Bar-Yosef
A1 Anat Bar-Ziv
A1 Doron Behar
A1 Shlomo Lipitz
A1 Tal Elkan Miller
A1 Anton T J Tool
A1 Taco W Kuijpers
A1 Timo K van den Berg
A1 Baruch Wolach
A1 Dirk Roos
A1 Elon Pras
YR 2018
UL http://jmg.bmj.com/content/55/3/166.abstract
AB Background Mutations in the NCF1 gene that encodes p47phox, a subunit of the NADPH oxidase complex, cause chronic granulomatous disease (CGD). In Kavkazi Jews, a c.579G>A (p.Trp193Ter) mutation in NCF1 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.Methods 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 p47phox expression.Results 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 NCF1 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 NCF1 c.579G>A mutation, we found five individuals with three complete NCF1 genes of which one was mutated (like the parents), and one individual with in addition a fusion gene of NCF1 with a pseudogene.Conclusion 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.