Clinical and Immunological Characterization of ICF Syndrome in Japan

Kamae, Chikako; Imai, Kohsuke; Kato, Tamaki; Okano, Toshio; Honma, Kenichi; Nakagawa, Noriko; Yeh, Tzu Wen; Noguchi, Emiko; Ohara, Akira; Shigemura, Tomonari; Takahashi, Hiroshi; Takakura, Shunichi; Hayashi, Masatoshi; Honma, Aoi; Watanabe, Seiichi; Shigemori, Tomoko; Ohara, Osamu; Sasaki, Hidetada; Kubota, Takeo; Morio, Tomohiro; Kanegane, Hirokazu; Nonoyama, Shigeaki

doi:10.1007/s10875-018-0559-y

Cited by 32 publications

(26 citation statements)

References 22 publications

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“…In vivo production of antibodies has been evaluated only in case of three previously reported patients [18,19,20] who all—similar to our patients—presented no or inadequate responses to vaccinations. Low B cell counts have been so far reported for 11 out of 27 patients for whom data are available (i.e., 41%) [9,13,18,19,20,21,22,23] including the here reported patient with hypogammaglobulinemia. Another rarely evaluated, though common abnormality among previously reported ICF2 patients, which we confirmed in our patients, is the substantially reduced CD27 + memory B cell count.…”

Section: Discussionmentioning

confidence: 53%

“…Humoral immunodeficiency with pronounced hypogammaglobulinemia appears common among patients with ICF2 [3,7,13]. However, only one among the here presented patients had clinically relevant hypogammaglobulinemia with severe IgG deficiency.…”

Section: Discussionmentioning

confidence: 85%

“…Immunodeficiency in ICF2 syndrome manifests with recurrent respiratory and/or gastrointestinal infections as a consequence of hypo- or agammaglobulinemia [3]. However, reports on fatal opportunistic fungal and/or viral infections as well as immunological profiles with T cell defects in some patients with ICF2 suggest that ICF2 can manifest as a combined immunodeficiency [3,13].…”

Section: Introductionmentioning

confidence: 99%

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Progressive Immunodeficiency with Gradual Depletion of B and CD4+ T Cells in Immunodeficiency, Centromeric Instability and Facial Anomalies Syndrome 2 (ICF2)

et al. 2019

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Immunodeficiency, centromeric instability and facial anomalies syndrome 2 (ICF2) is a rare autosomal recessive primary immunodeficiency disorder. So far, 27 patients have been reported. Here, we present three siblings with ICF2 due to a homozygous ZBTB24 gene mutation (c.1222 T>G, p. (Cys408Gly)). Immune deficiency in these patients ranged from late-onset combined immunodeficiency (CID) with severe respiratory tract infections and recurrent shingles to asymptomatic selective antibody deficiency. Evident clinical heterogeneity manifested despite a common genetic background, suggesting the pathogenic relevance of epigenetic modification. Immunological follow-up reveals a previously unidentified gradual depletion of B and CD4+ T cells in all three presented patients with transition of a common variable immunodeficiency (CVID)-like disease to late-onset-CID in one of them. Considering all previously published cases with ICF2, we identify inadequate antibody responses to vaccines and reduction in CD27+ memory B cells as prevalent immunological traits. High mortality among ICF2 patients (20%) together with the progressive course of immunodeficiency suggest that hematopoietic stem cell transplantation (HSCT) should be considered as a treatment option in due time.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

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Progressive Immunodeficiency with Gradual Depletion of B and CD4+ T Cells in Immunodeficiency, Centromeric Instability and Facial Anomalies Syndrome 2 (ICF2)

et al. 2019

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“…To date, 13 homozygous ZBTB24 nonsense variants have been identified from ICF2 patients, with seven variants located in the C2H2‐ZF domains, two variants in the BTB domain, one in the AT‐hook domain and three in between the AT‐hook and C2H2‐ZF domains (Figure a; Chouery et al, ; Conrad, Dawany, Sullivan, Devoto, & Kelsen, ; de Greef et al, ; Kamae et al, ; Nitta et al, ; van den Boogaard et al, ; Weemaes et al, ). These nonsense variants are predicted to result in proteins with a premature stop codon (Figure a).…”

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confidence: 99%

A functional assay to classify ZBTB24 missense variants of unknown significance

Vonk

Maarel

et al. 2019

Human Mutation

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Increasing use of next‐generation sequencing technologies in clinical diagnostics allows large‐scale discovery of genetic variants, but also results in frequent identification of variants of unknown significance (VUSs). Their classification into disease‐causing and neutral variants is often hampered by the absence of robust functional tests. Here, we demonstrate that a luciferase reporter assay, in combination with ChIP‐qPCR, reliably separates pathogenic ZBTB24 missense variants in the context of immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome from natural variants in healthy individuals and patients of other diseases. Application of our assay to two published ZBTB24 missense VUSs indicates that they are likely not to cause ICF2 syndrome. Furthermore, we show that rare gnomAD ZBTB24 missense variants in key residues of the C2H2‐ZF domain lead to a loss of function phenotype that resembles ICF2, suggesting that these individuals are carriers of ICF syndrome. In summary, we have developed a robust functional test to validate missense variants in ZBTB24.

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“…All ZBTB24 mutations found in ICF2 patients are predicted to disrupt at least one ZF motif (Alghamdi et al, 2018;Conrad, Dawany, Sullivan, Devoto, & Kelsen, 2017;de Greef et al, 2011;Kamae et al, 2018;Nitta et al, 2013;Sogkas et al, 2019;van den Boogaard et al, 2017;von Bernuth et al, 2014;Weemaes et al, 2013). Most of them are nonsense or frameshift mutations resulting in a truncated protein while the other two are mis-sense mutations in the ZF motifs (C383Y and C408G).…”

Section: Introductionmentioning

confidence: 99%

Identification of ZBTB24 protein domains and motifs for heterochromatin localization and transcriptional activation

2019

Self Cite

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Immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome is a rare autosomal recessive disorder caused by mutations in either DNMT3B, ZBTB24, CDCA7, HELLS or an unknown gene(s). Among the known causative genes, ZBTB24 encodes a member of the BTB‐zinc finger (ZF) transcription factor family. The protein possesses a BTB domain, an AT‐hook and eight C2H2 ZF motifs. All ZBTB24 mutations reported in ICF patients are predicted to disrupt at least one ZF motif. Here, we show that both AT‐hook and distinct ZF motifs, particularly the 6th motif, of human and mouse ZBTB24 proteins are important for their heterochromatin localization. On the other hand, the 6th and 7th ZF motifs, and not the AT‐hook or the BTB domain, of the human and mouse proteins are essential for transcriptional activation of CDCA7, another ICF causative gene and a known target of ZBTB24. By deletion analysis of the human CDCA7 promoter, we show that two motifs for ZBTB24 binding are important for transcriptional activation of this gene. These results reveal the evolutionarily conserved domains and motifs important for the biological function of ZBTB24, which provides a basis for understanding the molecular mechanisms underlying the pathogenesis of ICF syndrome.

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Clinical and Immunological Characterization of ICF Syndrome in Japan

Cited by 32 publications

References 22 publications

Progressive Immunodeficiency with Gradual Depletion of B and CD4+ T Cells in Immunodeficiency, Centromeric Instability and Facial Anomalies Syndrome 2 (ICF2)

Progressive Immunodeficiency with Gradual Depletion of B and CD4+ T Cells in Immunodeficiency, Centromeric Instability and Facial Anomalies Syndrome 2 (ICF2)

A functional assay to classify ZBTB24 missense variants of unknown significance

Identification of ZBTB24 protein domains and motifs for heterochromatin localization and transcriptional activation

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