Abstract
FBXO22 encodes an F-box protein, which acts as a substrate-recognition component of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase complex. Despite its known roles in the post-translational ubiquitination and degradation of specific substrates, including histone demethylases, the impact of FBXO22 on human development remains unknown. Here, we characterize a pleiotropic syndrome with prominent prenatal onset growth restriction and notable neurodevelopmental delay across 16 cases from 14 families. Through exome and genome sequencing, we identify four distinct homozygous FBXO22 variants with loss-of-function effects segregating with the disease: three predicted to lead to premature translation termination due to frameshift effects and a single-amino-acid-deletion variant, which, we show, impacts protein stability in vitro. We confirm that affected primary fibroblasts with a frameshift mutation are bereft of endogenous FBXO22 and show increased levels of the known substrate histone H3K9 demethylase KDM4B. Accordingly, we delineate a unique epigenetic signature for this disease in peripheral blood via long-read sequencing. Altogether, we identify and demonstrate that FBXO22 deficiency leads to a pleiotropic syndrome in humans, encompassing growth restriction and neurodevelopmental delay, the pathogenesis of which may be explained by broad chromatin alterations.