Missense variants in homeobox domain of PBX1 cause coracoclavicular ankylosis

There have been several reports on heterozygous loss of function variants in PBX1 associated with congenital anomalies of the kidney and urinary tract (CAKUT). We report three patients harboring de novo heterozygous missense variants in PBX1 , who did not have CAKUT, but instead presented with respiratory failure, developmental delay, and, the most important, a unique skeletal phenotype characterized by broad and short clavicles with coracoclavicular ankylosis and broad ischia with premature fusion of the ischiopubic synchondrosis. All the variants are clustered at the last portion of the homeobox domain. These phenotypes are consistent with mouse models with functional dysregulation in Pbx1 or its interacting factor, Emx2. This study reports a novel phenotype affecting the clavicle and ischia due to PBX1 variants and expands the clinical spectrum of PBX1-related disorder.