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J Med Genet. 2018 Mar;55(3):166-172. doi: 10.1136/jmedgenet-2017-105022. Epub 2018 Jan 13.

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

Author information

1
Sanquin Blood Cell Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
2
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.
3
The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
4
Genomic Research Center, Gene by Gene, Houston, Texas, USA.
5
Department of Gynecology, Sheba Medical Center, Ramat Gan, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
6
Department of Pediatric Hematology, Emma Children's Hospital Academic Medical Center, Amsterdam, The Netherlands.
#
Contributed equally

Abstract

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.

KEYWORDS:

Ncf1; P47phox; ashkenazi jews; chronic granulomatous disease; prenatal diagnosis

PMID:
29331982
DOI:
10.1136/jmedgenet-2017-105022
[Indexed for MEDLINE]

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