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Overgrowth syndromes (OGS) are a group of disorders in which all parameters of growth and physical development are above the mean for age and sex. We evaluated a series of 270 families from the Spanish Overgrowth Syndrome Registry with no known OGS. We identified onede novodeletion and three missense mutations inRNF125in six patients from four families with overgrowth, macrocephaly, intellectual disability, mild hydrocephaly, hypoglycemia, and inflammatory diseases resembling Sjögren syndrome.RNF125encodes an E3 ubiquitin ligase and is a novel gene of OGS. Our studies of the RNF125 pathway point to upregulation of RIG-I-IPS1-MDA5 and/or disruption of the PI3K-AKT and interferon signaling pathways as the putative final effectors.We have identified four mutations in a novel overgrowth gene, RNF125 (Fig A), in six patients with overgrowth, macrocephaly, intellectual disability, mild hydrocephaly, hypoglycaemia and inflammatory diseases resembling Sjögren syndrome. RNF125 encodes an E3 ubiquitin ligase. Functional characterisation showed that the mutations resulted in a dysregulation of RNF125 mRNA expression (Fig B). Additionally, clear differences in induction and degradation kinetics of RIG-I, a RNF125 target protein, between patients and control fibroblasts were observed (Fig C-E).