The Molecular Logic of Newly Detected Disease

Abstract

Newly detected diseases have accumulated rapidly over the past fifteen years, driven by exome and genome sequencing, by the intensely monitored cohorts created during the COVID-19 pandemic, and by culture-independent pathogen surveillance. This review examines twenty such entities and reconstructs the molecular mechanisms that define them. It covers monogenic autoinflammatory disease arising from failed ubiquitin homeostasis (VEXAS syndrome, haploinsufficiency of A20, otulipenia, PAAND), proteasome failure (PRAAS/CANDLE), interferonopathies caused by constitutive nucleic acid sensing (SAVI, COPA syndrome, MDA5 gain-of-function disease), inflammasomopathies driven by spontaneous caspase-1 activation (NLRC4 enterocolitis), and ADA2 deficiency as a deficiency vasculopathy. It then turns to syndromes defined in real time during the pandemic (MIS-C, vaccine-induced immune thrombotic thrombocytopenia, long COVID) and to newly detected pathogens, including a tick-borne phlebovirus, a shrew-borne henipavirus and the multidrug-resistant yeast Candida auris. For each entity, the review describes the responsible gene or pathogen, the aberrant biochemical step, the compartment and lineage in which the defect acts, and the downstream cytokine or cell-death programme, and it notes where competing mechanistic models remain unresolved. Three unifying principles emerge. First, most of these disorders displace the threshold at which a signal becomes an action rather than creating a new pathway, which explains why clinically dissimilar syndromes share interferon-stimulated gene signatures and respond to drugs chosen by pathway rather than by diagnosis. Second, homeostatic failure is converted into inflammation indirectly, through proteotoxic stress, protein mislocalisation and lytic cell death that are then sensed by inflammasomes and nucleic acid receptors. Third, compartment specificity and somatic mosaicism determine phenotype, as in VEXAS syndrome, where a myeloid-restricted UBA1 variant produces both marrow dysplasia and systemic inflammation that can be dissociated experimentally. Infectious examples add that severity depends as much on immune amplification as on microbial cytotoxicity, and that post-infectious syndromes may be sustained by antigen that is never fully cleared. Translation has followed these mechanisms: anticytokine biologics, JAK inhibition, haematopoietic transplantation and pathway-selective small molecules are now selected by lesion rather than by label. The principal remaining obstacle is recognition, since most patients with a defined molecular disease are still diagnosed as something else; the practical task is to move genotyping and pathway profiling earlier in the diagnostic pathway.