Human germline biallelic complete NFAT1 deficiency causes the triad of progressive joint contractures, osteochondromas, and susceptibility to B cell malignancy

Sharma, Mehul; Fu, Maggie P; Lu, Henry Y.; Sharma, Ashish; Modi, Bhavi P.; Michalski, Christina; Lin, Susan; Dalmann, Joshua; Salman, Areesha; Bel, Kate L. Del; Waqas, Meriam A.; Terry, Jefferson; Setiadi, Audi; Lavoie, Pascal M.; Wasserman, Wyeth W.; Mwenifumbo, Jill; Kobor, Michæl S.; Lee, Anna F.; Lehman, Anna; Cheng, Sylvia; Cooper, Anthony; Patel, Millan S.; Turvey, Stuart E.

doi:10.1101/2022.01.30.22269378

Cited by 3 publications

(1 citation statement)

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“…Trio whole exome sequencing (WES) was performed as previously described 34 . Briefly, WES was performed on genomic DNA extracted from the first patient (P1) and both his parents and a novel de novo predicted damaging STAT6 variant (c.1144G>C p.E382Q) was selected for further analysis.…”

Section: Methodsmentioning

confidence: 99%

Human Germline Heterozygous Gain-of-Function STAT6 Variants Cause Severe Allergic Disease

Sharma

Vaseghi‐Shanjani

et al. 2022

Preprint

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STAT6 (Signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. STAT6 mediates the biological effects of IL-4, a cytokine necessary for type 2 differentiation of T cells and B cell survival, proliferation and class switching to IgE. We have identificated two unrelated patients with a phenotype notable for their early-life onset of profound allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic esophagitis, elevated serum IgE, IgE-mediated food allergies, and vascular anomalies of the brain. Both patients harbored heterozygous de novo missense variants in the DNA binding domain of STAT6 (c.1144G>C, p.E382Q; and c.1256A>G, p.D419G). Functional studies established that both variants caused a gain-of-function (GOF) phenotype associated with enhanced phosphorylation and transcriptional activity of STAT6, in addition to increased transcript abundance of known STAT6 target genes and other genes implicated in allergic disease. JAK inhibitors decreased the enhanced STAT6 responses associated with both these STAT6 GOF variants. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of the first humans with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.

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Section: Methodsmentioning

confidence: 99%

Human Germline Heterozygous Gain-of-Function STAT6 Variants Cause Severe Allergic Disease

Sharma

Vaseghi‐Shanjani

et al. 2022

Preprint

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A germline heterozygous dominant negativeIKZF2variant causing syndromic primary immune regulatory disorder and ICHAD

Lu,

Vaseghi-Shanjani,

Lam

et al. 2023

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Monogenic defects that impair the control of inflammation and tolerance lead to profound immune dysregulation, including autoimmunity and atopy. Studying these disorders reveals important molecular and cellular factors that regulate human immune homeostasis and identifies potential precision medicine targets. Here, we provide a detailed immunological assessment of a pediatric patient with a recently discovered syndrome causing Immunodysregulation, Craniofacial anomalies, Hearing impairment, Athelia, and Developmental delay (or ICHAD syndrome). The immunodysregulation resulted in autoimmune hemolytic anemia (AIHA) and atopic dermatitis. The patient carried ade novogermline heterozygous c.406+540_574+13477dup;p.Gly136_Ser191dup variant inIKAROS family zinc finger 2(IKZF2), which encodes Helios. This variant led to reduced Helios protein expression and dominant interference of wild-type Helios-mediated repression of theIL2promoter. Multi-parameter flow cytometric analyses of patient peripheral blood mononuclear cells revealed strongly impaired natural killer cell differentiation and function, and increased CD8+T cell activation and cytokine secretion. Strikingly, patient CD4+T cells were hyperactive, produced elevated levels of nearly all T helper (TH) cytokines, and readily proliferated in response to stimulation. Patient regulatory T cells (Tregs) developed normally but aberrantly produced high levels of many THcytokines. Single-cell RNA sequencing revealed largely normal Tregs (albeit mostly memory), but naïve CD4+T cells that were more enriched in genes related to activation, proliferation, metabolism, and THdifferentiation. This work describes the immunological phenotype of one of the first reported cases of germline dominant negative Helios deficiency, expands our understanding of the pathogenesis of AIHA on a single cell level, and provides valuable insights into Helios function in a variety of lymphocyte subsets.

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Human ASXL1 Deficiency Causes Epigenetic Dysfunction, Combined Immunodeficiency and EBV–Associated Hodgkin Lymphoma

Fu,

Sharma,

Merrill

et al. 2023

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Inborn errors of immunity (IEI) are a group of disorders caused by deleterious variants in immune-related genes, including some that function as epigenetic regulators. Additional sex combs-like 1 (ASXL1) is an epigenetic modifier that has not previously been linked to an IEI. SomaticASXL1variants are found in clonal hematopoiesis and hematologic neoplasms, while heterozygous germline variants cause Bohring–Opitz syndrome. We present a new IEI caused by biallelic germline variants inASXL1. The patient had a complex and unusual history of disease progression notable for persistent cutaneous vaccine-strain rubella granulomas initially manifesting in early childhood, chronic macrocytosis and mild bone marrow cellular hypoplasia, and Epstein Barr virus– associated Hodgkin lymphoma in adolescence. Detailed immunophenotyping revealed progressive loss of B-cells, hypogammaglobinemia, and T-cell lymphopenia with severe skewing toward a memory phenotype and elevated expression of T-cell exhaustion and senescence markers. Molecular investigations confirmed ASXL1 protein deficiency in the patient’s T-cells and fibroblasts. The T-cells exhibited marked loss of DNA methylation, increased epigenetic aging, and CD8 T-cell dysfunction. These aberrations were ameliorated by lentivirus-mediated transduction with wild-typeASXL1, confirming the pathogenicity ofASXL1variants. This study defines a novel human IEI caused by ASXL1 deficiency, a diagnosis that should be considered in individuals with chronic viral infections, virus-associated hematologic malignancies, and combined immunodeficiency. Furthermore, our findings provide fresh insights into the mechanisms underlying the roles of human ASXL1 in T-cell function as well as in the development and maintenance of lymphomas.

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Human germline biallelic complete NFAT1 deficiency causes the triad of progressive joint contractures, osteochondromas, and susceptibility to B cell malignancy

Cited by 3 publications

References 92 publications

Human Germline Heterozygous Gain-of-Function STAT6 Variants Cause Severe Allergic Disease

Human Germline Heterozygous Gain-of-Function STAT6 Variants Cause Severe Allergic Disease

A germline heterozygous dominant negativeIKZF2variant causing syndromic primary immune regulatory disorder and ICHAD

Human ASXL1 Deficiency Causes Epigenetic Dysfunction, Combined Immunodeficiency and EBV–Associated Hodgkin Lymphoma

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