Issues

The inherited syndromic immunodysregulatory disorder MAGIS demonstrates the central role of G_αi2 regulation of chemotaxis in humans and a novel pathway by which G proteins regulate T cell activation. Here, the authors review MAGIS clinical features, current genetic and biochemical understanding, and future therapeutic considerations.

Incomplete penetrance in genetic disorders can be influenced by genetic variant quality, genetic and epigenetic modification, environment, and mosaicism.

This review unmasks the significant, yet understudied, role of innate lymphoid cells in inborn errors of immunity. The authors examine how these “behind the scenes” immune components contribute to monogenetic immune disorders, exploring their developmental defects, role in immune dysregulation, and potential as therapeutic targets.

Ataxia telangiectasia is a genetic disorder involving neurodegeneration, immunodeficiency, and cancer risk. It can be identified as incidental finding in newborn screening for SCID. Unfortunately, the clinical data and follow-up time are too limited, and the long-term effects on prognosis remain unclear, necessitating prospective studies.

This comprehensive review of cartilage-hair hypoplasia (CHH) by Vakkilainen summarizes 60 years of CHH research, covering genetic aspects, pathogenesis, clinical and laboratory features, as well as diagnostic and management considerations in this rare syndromic inborn error of immunity.

Andreakos et al. report the progress of the COVID Human Genetic Effort since its launch 5 years ago, with the aim to understand clinical variability, from resistance to severe outcomes, among individuals exposed to SARS-CoV-2. Their work revealed key mechanisms of pneumonia, MIS-C, and other manifestations, informing diagnostics, therapeutics, and preparedness for future pandemics.

This Perspective proposes universal genomic screening as a life-course strategy, using Mendelian susceptibility to mycobacterial disease as a model to demonstrate feasibility in high-consanguinity populations, where early genetic detection can enhance diagnosis, improve vaccine safety, and advance precision medicine.

Recurrent pneumonias and skin infections with persistent leukocytosis are concerning for leukocyte adhesion deficiency type-1. Intermittently normal neutrophil counts can be seen with partial deficiency. Compound heterozygotes, such as the patient described, may be predisposed for severe disease despite exhibiting moderate integrin expression profiles.

We describe two cases of severe refractory immune neutropenia: One with T-large granular lymphocyte leukemia and one with chronic idiopathic neutropenia. The JAK inhibitor ruxoltinib restored normal neutrophil counts and was well tolerated in both cases. Further investigation of ruxolitinib as a treatment for immune neutropenia is warranted.

A previous report described an inherited deficiency of IL-18BP, a soluble antagonist of IL-18, in an Algerian patient who died of fulminant viral hepatitis (FVH) A. We report here an Egyptian family with two siblings who died from FVH following infection with hepatitis A virus.

Recently developed in vitro technology was used to define the function of a previously uncharacterized STX11 mutation L135P present in a patient with atypical FHL. The results confirmed the FHL diagnosis and enabled clinicians to proceed with assurance to hematopoietic stem cell transplantation.

The presence of a second TNFRSF13B mutation, HLA class II markers, or multiple single nucleotide variants in patients helps to explain the incomplete penetrance of immunodeficiency in carriers of TNFRSF13B mutations.

We describe a novel heterozygous variant in AIRE in 3 individuals with mild APECED. This variant was validated as being pathogenic by a mechanism of negative dominance. This represents new cases of autosomal dominant APECED.

This epidemiological study describes CGD in Latin America. It highlights high infection risks, limited treatment options, and poor survival rates, especially for males with XL-CGD. The findings emphasize the need for better diagnosis, newborn screening, regional treatment guidelines, and expanded access to effective therapies.

Human OTULIN haploinsufficiency causes life-threatening staphylococcal disease, but the genotypic and phenotypic spectrum of the disorder remains largely unknown. We describe and characterize six unrelated patients with OTULIN haploinsufficiency, in whom severe necrosis followed infectious and/or traumatic triggers.

This study identifies a novel heterozygous USB1 variant (p.P44L) in a patient with hypogammaglobulinemia and low neutrophil counts, showing altered protein localization and function. Functional assays and zebrafish models reveal its impact on immune cells and pigmentation, expanding USB1-related disease understanding.

A novel mutation in ORAI1 results in constitutive CRAC channel activation while abolishing stimulation-induced channel opening. The mutation is associated with severe immune dysregulation, altered T and NK cell phenotypes and function, and attenuated CD8⁺ T effector memory cell function.