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.
- chronic granulomatous disease
- prenatal diagnosis
- ashkenazi jews
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DR and EP contributed equally.
MDB and RG contributed equally.
Contributors MdB, DB, SL, TEM, DR and EP designed the study. MdB, RG, KvL, HRW, MD, YB-Y, AB-Z and ATJT conducted experiments. DB, SL, TEM, TWK, TKvdB, BW, DR and EP supervised the study. DR and EP wrote the manuscript and are responsible for the overall content.
Competing interests None declared.
Patient consent Guardian consent obtained.
Ethics approval Academic Medical Center Amsterdam.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All data obtained are included in the manuscript.