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

Martin De Boer, Ronit Gavrieli, Karin van Leeuwen, Haike Reznik Wolf, Maya Dushnitzki, Yifaat Bar-Yosef, Anat Bar-Ziv, Doron Behar, Shlomo Lipitz, Tal Elkan Miller, Anton T J Tool, Taco W Kuijpers, Timo K van den Berg, Baruch Wolach, Dirk Roos, Elon Pras

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)166-172
Number of pages7
JournalJournal of Medical Genetics
Volume55
Issue number3
DOIs
Publication statusPublished - Mar 2018

Cite this

De Boer, M., Gavrieli, R., van Leeuwen, K., Wolf, H. R., Dushnitzki, M., Bar-Yosef, Y., ... Pras, E. (2018). A false-carrier state for the c.579G>A mutation in the NCF1 gene in Ashkenazi Jews. Journal of Medical Genetics, 55(3), 166-172. https://doi.org/10.1136/jmedgenet-2017-105022
De Boer, Martin ; Gavrieli, Ronit ; van Leeuwen, Karin ; Wolf, Haike Reznik ; Dushnitzki, Maya ; Bar-Yosef, Yifaat ; Bar-Ziv, Anat ; Behar, Doron ; Lipitz, Shlomo ; Miller, Tal Elkan ; Tool, Anton T J ; Kuijpers, Taco W ; van den Berg, Timo K ; Wolach, Baruch ; Roos, Dirk ; Pras, Elon. / A false-carrier state for the c.579G>A mutation in the NCF1 gene in Ashkenazi Jews. In: Journal of Medical Genetics. 2018 ; Vol. 55, No. 3. pp. 166-172.
@article{254c1a8892574511a7f932f230db0ab5,
title = "A false-carrier state for the c.579G>A mutation in the NCF1 gene in Ashkenazi Jews",
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.",
author = "{De Boer}, Martin and Ronit Gavrieli and {van Leeuwen}, Karin and Wolf, {Haike Reznik} and Maya Dushnitzki and Yifaat Bar-Yosef and Anat Bar-Ziv and Doron Behar and Shlomo Lipitz and Miller, {Tal Elkan} and Tool, {Anton T J} and Kuijpers, {Taco W} and {van den Berg}, {Timo K} and Baruch Wolach and Dirk Roos and Elon Pras",
note = "{\circledC} Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.",
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De Boer, M, Gavrieli, R, van Leeuwen, K, Wolf, HR, Dushnitzki, M, Bar-Yosef, Y, Bar-Ziv, A, Behar, D, Lipitz, S, Miller, TE, Tool, ATJ, Kuijpers, TW, van den Berg, TK, Wolach, B, Roos, D & Pras, E 2018, 'A false-carrier state for the c.579G>A mutation in the NCF1 gene in Ashkenazi Jews' Journal of Medical Genetics, vol. 55, no. 3, pp. 166-172. https://doi.org/10.1136/jmedgenet-2017-105022

A false-carrier state for the c.579G>A mutation in the NCF1 gene in Ashkenazi Jews. / De Boer, Martin; Gavrieli, Ronit; van Leeuwen, Karin; Wolf, Haike Reznik; Dushnitzki, Maya; Bar-Yosef, Yifaat; Bar-Ziv, Anat; Behar, Doron; Lipitz, Shlomo; Miller, Tal Elkan; Tool, Anton T J; Kuijpers, Taco W; van den Berg, Timo K; Wolach, Baruch; Roos, Dirk; Pras, Elon.

In: Journal of Medical Genetics, Vol. 55, No. 3, 03.2018, p. 166-172.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - A false-carrier state for the c.579G>A mutation in the NCF1 gene in Ashkenazi Jews

AU - De Boer, Martin

AU - Gavrieli, Ronit

AU - van Leeuwen, Karin

AU - Wolf, Haike Reznik

AU - Dushnitzki, Maya

AU - Bar-Yosef, Yifaat

AU - Bar-Ziv, Anat

AU - Behar, Doron

AU - Lipitz, Shlomo

AU - Miller, Tal Elkan

AU - Tool, Anton T J

AU - Kuijpers, Taco W

AU - van den Berg, Timo K

AU - Wolach, Baruch

AU - Roos, Dirk

AU - Pras, Elon

N1 - © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

PY - 2018/3

Y1 - 2018/3

N2 - 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.

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.

U2 - 10.1136/jmedgenet-2017-105022

DO - 10.1136/jmedgenet-2017-105022

M3 - Article

VL - 55

SP - 166

EP - 172

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 3

ER -

De Boer M, Gavrieli R, van Leeuwen K, Wolf HR, Dushnitzki M, Bar-Yosef Y et al. A false-carrier state for the c.579G>A mutation in the NCF1 gene in Ashkenazi Jews. Journal of Medical Genetics. 2018 Mar;55(3):166-172. https://doi.org/10.1136/jmedgenet-2017-105022