DNA‐Binding domain mutations confer severe outcome at an early age among STAT1 gain‐of‐function patients

Abstract

Background: STAT1 gain-of-function (GOF) is an immune dysregulatory disorder with poorly studied genotype-phenotype correlation, impeding prognostication and early intervention. Given previous mechanistic studies, as well as anecdotal clinical reports, we sought to systematically determine whether DNA-binding domain (DBD) mutations in STAT1 result in a different phenotype than mutations in other gene domains.Methods: Negative prognostic features previously identified by the International STAT1 GOF Study Group (invasive infections, intracranial aneurysms, and malignancy), as well as other clinical features and mortality, were compared within a cohort of 30 patients with STAT1 GOF diagnosed at our center, consisting of 9 patients with DBD mutations and 21 patients with non-DBD mutations. We subsequently reanalyzed mortality data from a large, previously-published 274-patient cohort by the International STAT1 GOF Study Group.Results: While no differences were noted with respect to malignancy or symptomatic aneurysms, invasive /opportunistic infections were substantially more common among DBD patients, as were sinopulmonary infections, bronchiectasis, enteropathy, endocrinopathies, lymphoproliferative manifestations, and recurrent fevers/HLH. DBD patients also had a lower probability of survival and younger age of mortality compared with non-DBD patients. Our re-evaluation of the published data from the International STAT1 GOF Study Group revealed a similar finding of earlier mortality among patients harboring DBD mutations. Conclusion:We report that STAT1 GOF patients with DBD mutations may be regarded as a unique subgroup, impacted more by early-onset profound combined immunodeficiency and with earlier mortality. These findings may impact clinical decision making with respect to early intervention, and in particular hematopoietic stem cell transplant considerations, in such patients.

Human STAT1 gain of function with chronic mucocutaneous candidiasis: A comprehensive review for strengthening the connection between bedside observations and laboratory research

“…These include endocrinopathies, autoimmune gastrointestinal diseases, autoimmune cytopenia, intestinal lung disease, and/or IPEX-like syndrome, which contribute to severe clinical phenotypes, often necessitating HSCT. 18,78,79 Among other complications, bronchiectasis (21%) was observed, primarily due to persistent and/or recurrent lower respiratory infections. 38 Dysphagia resulting from long-term gastroesophageal candidiasis occurred in 9% of cases.…”

“…Meanwhile, it is known that patients with the STAT1 T385M variant have a higher prevalence of autoimmunity phenotypes, such as endocrinopathies, autoimmune gastrointestinal disease, autoimmune cytopenia, intestinal lung disease, and/or IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X‐linked)‐like syndrome. These conditions lead to severe clinical phenotypes, and in some cases, the patients require hematopoietic stem cell transplantation (HSCT) 18,78,79 . Furthermore, the infectious features observed in patients with the STAT1 T385M variant tend to manifest autoimmune features 79 .…”

A Cas9-fusion proximity-based approach generates anIrak1-Mecp2tandem duplication mouse model for the study of MeCP2 duplication syndrome

“…This suggests that perhaps the precise effect of MeCP2 aberrations could be dosedependent, whereby an overexpression up to 5-fold in leads to a different effect than a 2-fold increase. Clinically, chronic immune skewing toward Th1 has the potential to result in viral lung infections, chronic lung inflammation and impairment in immune memory, as noted for example in some STAT1 gain-of-function patients (Scott et al, 2022). However, further testing and sampling of both serum and tissue samples from acutely infected MDS patients as well as the Mecp2 Dup mice will be required to further address this issue.…”

“Inborn errors of immunity: An expanding horizon through a multitude of biological pathways”

“…The validity of the disease categories derived from this exercise relies heavily on the continuous confirmation and updating of such phenotypic features. In this context, the virtual issue on “Inborn Errors of Immunity” aims at providing the readers of PAI a collection of topical reviews on some of the major immunological pathways that can be affected by pathological genetic variants causing IEIs and a selection of original articles highlighting clinical observations from cohort studies of well‐known conditions, as well as original discoveries that extend the genetic and clinical features of less commonly observed IEIs 1–17 …”

“…In this context, the virtual issue on "Inborn Errors of Immunity" aims at providing the readers of PAI a collection of topical reviews on some of the major immunological pathways that can be affected by pathological genetic variants causing IEIs and a selection of original articles highlighting clinical observations from cohort studies of well-known conditions, as well as original discoveries that extend the genetic and clinical features of less commonly observed IEIs. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] In their review of IEIs caused by defects in the DNA damage response pathways, Fournier and Colleagues 3 Additional reviews of the areas of IEIs characterized by defects of actin cytoskeletal dynamics, the JAK-STAT pathways, and type I interferon disorders have been commissioned and will be available in the near future. These works will complement the current collection and provide the readers of PAI with additional timely updates and perspectives on the scientific and clinical aspects of some of the major disease subgroups in the field of IEIs.…”