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Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

Usher syndrome (USH) is the most common cause of deafblindness. USH is autosomal recessively inherited and characterized by rod‐cone dystrophy or retinitis pigmentosa (RP), often accompanied by sensorineural hearing loss. Variants in >15 genes have been identified as causative for clinically and genetically distinct subtypes. Among the ultra‐rare and recently discovered genes is ARSG, coding for the lysosomal sulfatase Arylsulfatase G. This subtype was assigned as "USH IV" with a late onset of RP and usually late‐onset progressive SNHL without vestibular involvement. Here, we describe nine new subjects and the clinical description of four cases with the USH IV phenotype bearing seven novel and two known pathogenic variants. Functional experiments indicated the complete loss of sulfatase enzymatic activity upon ectopic expression of mutated ARSG cDNA. Interestingly, we identified a homozygous missense variant, p.(Arg99His), previously described in dogs with neuronal ceroid lipofuscinosis. Our study expands the genetic landscape of ARSG‐USH IV and the number of known subjects by more than 30%. These findings highlight that USH IV likely has been underdiagnosed and emphasize the need to test molecularly unresolved subjects with deafblindness syndrome. Finally, testing of ARSG should be considered for the genetic work‐up of apparent isolated inherited retinal diseases. [ABSTRACT FROM AUTHOR]

Pathogenic biallelic variants in the BLM/RECQL3 gene cause a rare autosomal recessive disorder called Bloom syndrome (BS). This syndrome is characterized by severe growth delay, immunodeficiency, dermatological manifestations and a predisposition to a wide variety of cancers, often multiple and very early in life. Literature shows that the main mode of BLM inactivation is protein translation termination. We expanded the molecular spectrum of BS by reporting the first deep intronic variant causing intron exonisation. We describe a patient with a clinical phenotype of BS and a strong increase in sister chromatid exchanges (SCE), who was found to be compound heterozygous for a novel nonsense variant c.3379C>T, p.(Gln1127Ter) in exon 18 and a deep intronic variant c.3020‐258A>G in intron 15 of the BLM gene. The deep intronic variant creates a high‐quality de novo donor splice site, which leads to retention of two intron segments. Both pseudo‐exons introduce a premature stop codon into the reading frame and abolish BLM protein expression, confirmed by Western Blot analysis. These findings illustrate the role of non‐coding variation in Mendelian disorders and herewith highlight an unmet need in routine testing of Mendelian disorders, being the added value of RNA‐based approaches to provide a complete molecular diagnosis. [ABSTRACT FROM AUTHOR]

Summary: GATA2 deficiency, first described in 2011, is a bone marrow failure disorder resulting in a complex haematological and immunodeficiency syndrome characterised by cytopenias, severe infections, myelodysplasia and leukaemia. The only curative treatment is allogeneic haematopoietic stem cell transplantation (HSCT). Although knowledge on this syndrome has greatly expanded, in clinical practice many challenges remain. In particular, guidelines on optimal donor and stem cell source and conditioning regimens regarding HSCT are lacking. Additionally, genetic analysis of GATA2 is technically cumbersome and could easily result in false‐negative results. With this report, we wish to raise awareness of these pitfalls amongst physicians dealing with haematological malignancies and primary immunodeficiencies. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 16-year-old boy with recurrent episodes of fever, without any respiratory problems but with concomitant abdominal and sometimes thoracic pain and arthralgia. It mentions that genetic evaluation was performed to identify the molecular cause of Primary ciliary dyskinesia (PCD) as well as Familial Mediterranean fever (FMF). It informs that the patient was treated with colchicine.

Human inborn errors of immunity (IEI) represent a diverse group of genetic disorders affecting the innate and/or adaptive immune system. Some IEI entities comprise defects in DNA repair factors, resulting in (severe) combined immunodeficiencies, bone marrow failure, predisposition to malignancies, and potentially resulting in radiosensitivity (RS). While other IEI subcategories such as common variable immunodeficiency (CVID) and immune dysregulation disorders also associate with lymphoproliferative and malignant complications, the occurrence of RS phenotypes in the broader IEI population is not well characterized. Nonetheless, identifying RS in IEI patients through functional testing is crucial to reconsider radiation-related therapeutic protocols and to improve overall patient management. This study aimed to investigate chromosomal RS in a diverse cohort of 107 IEI patients using the G0 cytokinesis-block micronucleus (MN) assay. Our findings indicate significant variability in RS across specific genetic and phenotypical subgroups. Severe RS was detected in all ataxia-telangiectasia (AT) patients, a FANCI deficient and ERCC6L2 deficient patient, but not in any other IEI patient included in this cohort. Age emerged as an influencing factor for both spontaneous and radiation-induced MN yields, while the manifestation of additional clinical features, including infection susceptibility, immune dysregulation, or malignancies did not associate with increased MN levels. Our extensive analysis of RS in the IEI population underscores the clinical importance of RS assessment in AT patients and supports RS testing in all IEI patients suspected of having a DNA repair disorder associated with RS., Competing Interests: Declarations. Ethics Approval: This study was reviewed and approved by the Ethics Committee of the Ghent University Hospital (reference no. 2012/593, 2019/0461 and 2019/1565). Written informed consent was obtained from all participants in this study, in accordance with the 1975 Helsinki Declaration. Conflicts of Interest: The authors declare no competing interests., (© 2025. The Author(s).)

The etiology of primary antibody deficiencies is largely unknown. Beside rare monogenic forms, the majority of cases seem to have a more complex genetic basis. Whereas common variable immunodeficiency has been investigated in depth, there are only a few reports on milder primary antibody deficiencies such as idiopathic primary hypogammaglobulinemia and IgG subclass deficiency. We performed flow cytometric immunophenotyping in 33 patients with common variable immunodeficiency, 23 with idiopathic primary hypogammaglobulinemia and 21 with IgG subclass deficiency, as well as in 47 asymptomatic first-degree family members of patients and 101 unrelated healthy controls. All three groups of patients showed decreased memory B- and naïve T-cell subsets and decreased B-cell activating factor receptor expression. In contrast, circulating follicular helper T-cell frequency and expression of inducible T-cell co-stimulator and chemokine receptors were only significantly altered in patients with common variable immunodeficiency. Asymptomatic first-degree family members of patients demonstrated similar, albeit intermediate, alterations in naïve and memory B- and T-cell subsets. About 13% of asymptomatic relatives had an abnormal peripheral B-cell composition. Furthermore, asymptomatic relatives showed decreased levels of CD4 + recent thymic emigrants and increased central memory T cells. Serum IgG and IgM levels were also significantly lower in asymptomatic relatives than in healthy controls. We conclude that, in our cohort, the immunophenotypic landscape of primary antibody deficiencies comprises a spectrum, in which some alterations are shared between all primary antibody deficiencies whereas others are only associated with common variable immunodeficiency. Importantly, asymptomatic first-degree family members of patients were found to have an intermediate phenotype for peripheral B- and T-cell subsets., (Copyright© Ferrata Storti Foundation.)