In FAS deficiency, lymphoproliferation is driven by FAS-controlled T cells (FCT), yet underlying metabolic programs remain unclear. Using EBV-activated effector T cells as a benchmark, Maccari et al. show that FCT display comparably heightened glycolysis, but a metabolic program uncoupled from T-BET expression and IFNγ production.

Riley, Kotzin et al. screened 43,731 adult exomes and identified six individuals with STING gain-of-function mutations that cause pediatric SAVI. These adults presented with phenotypes ranging from lupus and polychondritis to clinical non-penetrance, none previously diagnosed with SAVI. This establishes AO-SAVI, suggesting that monogenic inborn errors of immunity may be underrecognized in adults.

Griscelli syndrome type 2 typically presents with hypopigmentation and HLH, but some patients retain normal pigmentation. Tanaka et al. functionally characterize compound heterozygous RAB27A variants in Japanese patients, showing allele-specific dissociation of melanosome transport and cytotoxic function, underscoring the need for integrated genetic and functional diagnosis.

Moreno-Corona et al. identify compound-heterozygous WDR75 variants in a patient with hypogammaglobulinemia and autism spectrum disorder. These variants impair pre-ribosomal RNA processing and trigger nucleolar stress, suggesting a new ribosomopathy.

The mechanisms underlying thymic dysfunction in the 22q11.2 deletion syndrome are poorly defined. In this study, Hennings et al. integrated spatial transcriptomic and proteomic analyses of thymus tissue from patients with 22q11.2 deletion syndrome to identify fibroblast-driven collagen expansion and alterations in medullary niches.

Longitudinal profiling of 136 newborns shows thymic output peaks at 3–4 mo, correlating with plasma RANKL, lymphotoxin-α, and the TCRD variant rs2204985. In thymic tissue, RANKL tracks medullary—but not cortical—epithelial cellularity, suggesting a microenvironmental basis for thymopoiesis.

Gunderman et al. share the second report of X-linked SEPTIN6-related disease in two brothers identified by SCID newborn screening. Findings include congenital neutropenia, absent circulating B cells, marrow mature myeloid, and rare plasma cell accumulation, as well as tetraploidy, with disease reversal following myeloablative HSCT. Xenograft studies implicate SEPTIN6 playing a role in lymphocyte development.