A false-carrier state for the c.579G>A mutation in the NCF1 gene in Ashkenazi Jews

Background Mutations in the NCF1 gene that encodes p47 phox , a subunit of the NADPH oxidasecomplex, 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 oxidaseactivity and p47 phox 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 familywas consistent with the fetusinheriting both carrier alleles from the parents. MLPA indicated four complete NCF1 genes in the fetusand 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 geneof NCF1 with a pseudogene. Conclusion These results point to the existence of a ‘false-carrier’ state in Ashkenazi Jewsand have wide implications regarding pre-pregnancy screening in this and other population groups.