Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.

Rare diseases of epigenetic origin: Challenges and opportunities.

Rare diseases (RDs), more than 80% of which have a genetic origin, collectively affect approximately 350 million people worldwide. Progress in next-generation sequencing technology has both greatly accelerated the pace of discovery of novel RDs and provided more accurate means for their diagnosis. RDs that are driven by altered epigenetic regulation with an underlying genetic basis are referred to as rare diseases of epigenetic origin (RDEOs). These diseases pose unique challenges in research, as they often show complex genetic and clinical heterogeneity arising from unknown gene-disease mechanisms. Furthermore, multiple other factors, including cell type and developmental time point, can confound attempts to deconvolute the pathophysiology of these disorders. These challenges are further exacerbated by factors that contribute to epigenetic variability and the difficulty of collecting sufficient participant numbers in human studies. However, new molecular and bioinformatics techniques will provide insight into how these disorders manifest over time. This review highlights recent studies addressing these challenges with innovative solutions. Further research will elucidate the mechanisms of action underlying unique RDEOs and facilitate the discovery of treatments and diagnostic biomarkers for screening, thereby improving health trajectories and clinical outcomes of affected patients.

Associations of peripheral blood DNA methylation and estimated monocyte proportion differences during infancy with toddler attachment style.

Attachment is a motivational system promoting felt security to a caregiver resulting in a persistent internal working model of interpersonal behavior. Attachment styles are developed in early social environments and predict future health and development outcomes with potential biological signatures, such as epigenetic modifications like DNA methylation (DNAm). Thus, we hypothesized infant DNAm would associate with toddler attachment styles. An epigenome-wide association study (EWAS) of blood DNAm from 3-month-old infants was regressed onto children's attachment style from the Strange Situation Procedure at 22-months at multiple DNAm Cytosine-phosphate-Guanine (CpG) sites. The 26 identified CpGs associated with proinflammatory immune phenotypes and cognitive development. In post-hoc analyses, only maternal cognitive-growth fostering, encouraging intellectual exploration, contributed. For disorganized children, DNAm-derived cell-type proportions estimated higher monocytes -cells in immune responses hypothesized to increase with early adversity. Collectively, these findings suggested the potential biological embedding of both adverse and advantageous social environments as early as 3-months-old.

Human complete NFAT1 deficiency causes a triad of joint contractures, osteochondromas, and B-cell malignancy.

The discovery of humans with monogenic disorders has a rich history of generating new insights into biology. Here we report the first human identified with complete deficiency of nuclear factor of activated T cells 1 (NFAT1). NFAT1, encoded by NFATC2, mediates calcium-calcineurin signals that drive cell activation, proliferation, and survival. The patient is homozygous for a damaging germline NFATC2 variant (c.2023_2026delTACC; p.Tyr675Thrfs∗18) and presented with joint contractures, osteochondromas, and recurrent B-cell lymphoma. Absence of NFAT1 protein in chondrocytes caused enrichment in prosurvival and inflammatory genes. Systematic single-cell-omic analyses in PBMCs revealed an environment that promotes lymphomagenesis with accumulation of naïve B cells (enriched for oncogenic signatures MYC and JAK1), exhausted CD4+ T cells, impaired T follicular helper cells, and aberrant CD8+ T cells. This work highlights the pleiotropic role of human NFAT1, will empower the diagnosis of additional patients with NFAT1 deficiency, and further defines the detrimental effects associated with long-term use of calcineurin inhibitors.

Prognostic role of diuretic failure in determining mortality for patients hospitalized with acute decompensated heart failure.

BACKGROUND: Worsening heart failure (WHF) is defined as persistent or worsening symptoms of heart failure that require an escalation in intravenous therapy or initiation of mechanical and ventilatory support during hospitalization. We assessed a simplified version of WHF called diuretic failure (DF), defined as an escalation of loop diuretic dosing after 48 h, and assessed its effects on mortality and rehospitalizations at 60-days. METHODS: We conducted a multicenter retrospective study between December 1, 2017 and January 1, 2020. We identified 1389 patients of which 6.4% experienced DF. RESULTS: There was a significant relationship between DF and cumulative rates of 60-day mortality and 60-day rehospitalizations (p = 0.0002 and p = 0.0214). After multivariate adjustment, DF was associated with longer hospital stay (p < 0.0001), increased rate of 60-day mortality (p = 0.026), 60-day rehospitalizations (p = 0.036), and a composite outcome of 60-day mortality and 60-day cardiac rehospitalizations (p = 0.018). CONCLUSIONS: DF has a strong relationship with adverse heart failure outcomes suggesting it is a simple yet robust prognostic indicator which can be used in real time to identify high-risk patients during hospitalization and beyond.