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

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

doi:10.1136/jmedgenet-2017-105022

Cited by 6 publications

(2 citation statements)

References 19 publications

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“…This assay simply quantitates GTGT and DGT sequences, regardless of whether these sequences are within their respective genes or within "fusion" genes that result from DNA recombination. 14,15 Despite the diversity of possible gene products, the ddPCR data are sufficient to segregate the patients, carriers, and kindred in most p47 phox CGD families. Advanced technologies such as multiplex ligation-dependent probe amplification are required to delineate the specific NCF1 defect.…”

Section: Genotyping With Ddpcrmentioning

confidence: 99%

NCF1 (p47phox)–deficient chronic granulomatous disease: comprehensive genetic and flow cytometric analysis

et al. 2019

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Mutations in NCF1 (p47phox) cause autosomal recessive chronic granulomatous disease (CGD) with abnormal dihydrorhodamine (DHR) assay and absent p47phox protein. Genetic identification of NCF1 mutations is complicated by adjacent highly conserved (>98%) pseudogenes (NCF1B and NCF1C). NCF1 has GTGT at the start of exon 2, whereas the pseudogenes each delete 1 GT (ΔGT). In p47phox CGD, the most common mutation is ΔGT in NCF1 (c.75_76delGT; p.Tyr26fsX26). Sequence homology between NCF1 and its pseudogenes precludes reliable use of standard Sanger sequencing for NCF1 mutations and for confirming carrier status. We first established by flow cytometry that neutrophils from p47phox CGD patients had negligible p47phox expression, whereas those from p47phox CGD carriers had ∼60% of normal p47phox expression, independent of the specific mutation in NCF1. We developed a droplet digital polymerase chain reaction (ddPCR) with 2 distinct probes, recognizing either the wild-type GTGT sequence or the ΔGT sequence. A second ddPCR established copy number by comparison with the single-copy telomerase reverse transcriptase gene, TERT. We showed that 84% of p47phox CGD patients were homozygous for ΔGT NCF1. The ddPCR assay also enabled determination of carrier status of relatives. Furthermore, only 79.2% of normal volunteers had 2 copies of GTGT per 6 total (NCF1/NCF1B/NCF1C) copies, designated 2/6; 14.7% had 3/6, and 1.6% had 4/6 GTGT copies. In summary, flow cytometry for p47phox expression quickly identifies patients and carriers of p47phox CGD, and genomic ddPCR identifies patients and carriers of ΔGT NCF1, the most common mutation in p47phox CGD.

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Section: Genotyping With Ddpcrmentioning

confidence: 99%

NCF1 (p47phox)–deficient chronic granulomatous disease: comprehensive genetic and flow cytometric analysis

et al. 2019

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“…The variant is also frequent among Ashkenazi Jews although Ashkenazi chronic granulomatous disease patients with this variant have not been described [8, 9]. Carrier screening based on a uniform expanded pan Israeli preconception screening panel of an Ashkenazi couple while the woman was pregnant revealed that both spouses were heterozygotes the variant c.579G > A, and prenatal diagnosis was performed [15]. The fetus inherited both carrier alleles but was not affected; having substantial oxidase activity revealed by the analysis of fetal leucocytes obtained by cordocentesis.…”

Section: Population-specific Screening Program or Universal Screeningmentioning

confidence: 99%

The Israeli national population program of genetic carrier screening for reproductive purposes. How should it be continued?

Zlotogora

2019

Isr J Health Policy Res

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The Israeli population genetic screening program for reproductive purposes, is a population-specific screening that includes all known, severe diseases and relatively frequent in a specific population (carrier frequency at or above 1:60 and/or disease frequency at or above 1 in 15,000 live births). The carrier screening program is free of charge and offers testing according to disease frequency in the different groups within the population.The extraordinary technical changes that occurred in the last decade as well as the changes in the type of marriages within the Israeli population necessitate a revision in the basis of the program.The screening should include instead of only the relatively frequent variants, all the variants that were reported among patients causing a severe disease for which the natural history is well known without regard of their frequency. The population-specific screening that determine which variants are included according to the origin of the couple should be abandoned for a general screening including either all the Jewish population or all the Israeli Arab population.

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Chronic Granulomatous Disease

Roos

2019

Methods in Molecular Biology

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Introduction: Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent, life-threatening bacterial and fungal infections of the skin, the airways, the lymph nodes, the liver, the brain and the bones. Frequently found pathogens are Staphylococcus aureus, Aspergillus species, Klebsiella species, Burkholderia cepacia, Serratia marcescens and Salmonella species. Sources of data: CGD is a rare (∼1:250 000 individuals) disease caused by mutations in any one of the five components of the NADPH oxidase in phagocytic leucocytes. This enzyme generates superoxide and is essential for intracellular killing of pathogens by phagocytes. Areas of agreement: CGD patients suffer not only from life-threatening infections, but also from excessive inflammatory reactions. Areas of controversy: Neither the cause of these inflammatory reactions nor the way to treat them is clear. Areas timely for developing research: Patient selection for and timing of bone marrow transplantation along with gene therapy.

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

Abstract: 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.

Cited by 6 publications

References 19 publications

NCF1 (p47phox)–deficient chronic granulomatous disease: comprehensive genetic and flow cytometric analysis

NCF1 (p47phox)–deficient chronic granulomatous disease: comprehensive genetic and flow cytometric analysis

The Israeli national population program of genetic carrier screening for reproductive purposes. How should it be continued?

Chronic Granulomatous Disease

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