Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency

Vavassori, Stefano; Chou, Janet; Faletti, Laura; Haunerdinger, Veronika; Opitz, Lennart; Joset, Pascal; Fraser, Christopher; Prader, Seraina; Gao, Xianfei; Schuch, Luise A.; Wagner, Matias; Hoefele, Julia; Maccari, Maria Elena; Zhu, Ying; Elakis, George; Gabbett, Michael T.; Forstner, Maria; Omran, Heymut; Kaiser, Thomas; Keßler, Christina; Olbrich, Heike; Frosk, Patrick; Almutairi, Abduarahman; Platt, Craig D.; Elkins, Megan; Weeks, Sabrina; Rubin, Tamar; Planas, Raquel; Marchetti, Tommaso; Koovely, Danil; Klämbt, Verena; Soliman, Neveen A.; Hardenberg, Sandra von; Klemann, Christian; Baumann, Ulrich; Lenz, Dominic; Klein‐Franke, Andreas; Schwemmle, Martin; Huber, Michael; Sturm, Ekkehard; Hartleif, Steffen; Häffner, Karsten; Gimpel, Charlotte; Brotschi, Barbara; Laube, Guido F.; Güngör, Tayfun; Buckley, Michael F.; Kottke, Raimund; Staufner, Christian; Hildebrandt, Friedhelm; Reu‐Hofer, Simone; Moll, Solange; Weber, Achim; Kaur, Hundeep; Ehl, Stephan; Hiller, Sebastian; Geha, Raif S.; Roscioli, Tony; Griese, Matthias; Schmid, Jana Pachlopnik

doi:10.1016/j.jaci.2021.03.045

Cited by 57 publications

(65 citation statements)

References 38 publications

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“…This is consistent with the notion that ZNFX1 disease causes multiorgan dysfunction. 4 The neurological phenotype observed in four of our patients is in line with the previous literature, 3,4 however, its etiology is unclear. Leukoencephalopathy and brain calcifications have been described in evidently immune-induced diseases with dysregulated ISG expression, for example, Aicardi-Goutières syndrome.…”

Section: Discussionsupporting

confidence: 89%

“…To date, 13 different variants have been described in patients with ZNFX1-related immunodeficiency (Figure 1). 3,4 Similarly to changes observed in our patients, these hitherto-reported alterations are distributed in all three domains and include missense, nonsense, and frameshift variants. The two latter types of changes when situated in ZNFX1 exons 1-12 lead to a complete loss of protein product through nonsense-mediated mRNA decay (NMD), while the frameshift deletions in the last exon result in the synthesis of truncated protein.…”

Section: Discussionsupporting

confidence: 76%

“…Three of the previously reported patients had not experienced severe viral infection but rather an MSMD-like clinical manifestation, 3 while 12 other patients presented with severe infections by both RNA and DNA viruses. 4 Among our probands, infections with DNA/RNA viruses, bacteria, and fungi were reported. Hepatomegaly and splenomegaly were present in comparable percentages of our and previously reported patients (all with available data 7/9 vs. 11/15), while HLHlike episodes were less frequent in our patients (3/7 vs. 11/18).…”

Section: Discussionmentioning

confidence: 82%

“…9 ZNFX1 seems to participate in the post-transcriptional regulation of ISG mRNA stability, given that in the absence of ZNFX1 in patient-derived cells, the half-life of ISG mRNAs is extended upon stimulation with intracellular DNA. 4 ZNFX1-deficient mice are viable and without any obvious abnormalities but show increased viral replication in the lung and liver. 9 In humans, biallelic ZNFX1 variants cause a broader clinical presentation.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, ZNFX1 (zinc finger NFX1-type containing 1) was reported as a novel gene for recessively inherited immunodeficiency, characterized by severe viral infections or MSMD, and accompanied by monocytosis, neutrophilia, thrombocytopenia, hepatomegaly, and splenomegaly in 19 patients from 10 unrelated families. 3,4 To further investigate the role of variants in ZNFX1 in primary immunodeficiencies, we queried our in-house bio-databank 5 for rare homozygous/compound heterozygous changes in ZNFX1 and the relevant Human Phenotype Ontology (HPO) terms. We report nine additional patients from seven unrelated families with biallelic variants in ZNFX1 that share a broader immunological and hematological phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Biallelic ZNFX1 variants are associated with a spectrum of immuno‐hematological abnormalities

et al. 2021

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Biallelic changes in the ZNFX1 gene have been recently reported to cause severe familial immunodeficiency. Through a search of our bio/databank with information from genetic testing of >55 000 individuals, we identified nine additional patients from seven families with six novel homozygous ZNFX1 variants. Consistent with the previously described phenotype, our patients suffered from monocytosis, thrombocytopenia, hepatosplenomegaly, recurrent infections, and lymphadenopathy. The two most severely affected probands also had renal involvement and clinical presentations compatible with hemophagocytic lymphohistiocytosis. The disease was less lethal among our patients than previously reported. We identified two missense

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Biallelic ZNFX1 variants are associated with a spectrum of immuno‐hematological abnormalities

et al. 2021

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PhenomeCentral: 7 years of rare disease matchmaking

et al. 2022

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A major challenge in validating genetic causes for patients with rare diseases (RDs) is the difficulty in identifying other RD patients with overlapping phenotypes and variants in the same candidate gene. This process, known as matchmaking, requires robust data sharing solutions to be effective. In 2014 we launched PhenomeCentral, a RD data repository capable of collecting computer‐readable genotypic and phenotypic data for the purposes of RD matchmaking. Over the past 7 years PhenomeCentral's features have been expanded and its data set has consistently grown. There are currently 1615 users registered on PhenomeCentral, which have contributed over 12,000 patient cases. Most of these cases contain detailed phenotypic terms, with a significant portion also providing genomic sequence data or other forms of clinical information. Matchmaking within PhenomeCentral, and with connections to other data repositories in the Matchmaker Exchange, have collectively resulted in over 60,000 matches, which have facilitated multiple gene discoveries. The collection of deep phenotypic and genotypic data has also positioned PhenomeCentral well to support next generation of matchmaking initiatives that utilize genome sequencing data, ensuring that PhenomeCentral will remain a useful tool in solving undiagnosed RD cases in the years to come.

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Genetic aetiologies of acute liver failure

Hegarty,

Thompson

2024

J of Inher Metab Disea

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Acute liver failure (ALF) is a rare, rapidly evolving, clinical syndrome with devastating consequences where definitive treatment is by emergency liver transplantation. Establishing a diagnosis can be challenging and, historically, the cause of ALF was unidentified in up to half of children. However, recent technological and clinical advances in genomic medicine have led to an increasing proportion being diagnosed with monogenic aetiologies of ALF. The conditions encountered include a diverse group of inherited metabolic disorders each with prognostic and treatment implications. Often these disorders are clinically indistinguishable and may even mimic disorders of immune regulation or red cell disorders. Rapid genomic sequencing for children with ALF is, therefore, a key component in the diagnostic work up today. This review focuses on the monogenic aetiologies of ALF.

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Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency

Cited by 57 publications

References 38 publications

Biallelic ZNFX1 variants are associated with a spectrum of immuno‐hematological abnormalities

Biallelic ZNFX1 variants are associated with a spectrum of immuno‐hematological abnormalities

PhenomeCentral: 7 years of rare disease matchmaking

Genetic aetiologies of acute liver failure

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