Cenani-Lenz syndactyly syndrome (CLS) is an autosomal recessive skeletal disorder that results in malformation of the distal limb, commonly associated with kidney agenesis/hypoplasia.Recent studies have shown that CLS was caused by mutations in the low-density lipoprotein receptor-related protein 4 (LRP4) gene and dysregulated canonical WNT signaling pathway.We have identified a consanguineous Jordan family with one member affected by CLS.The proband presents with a consistent expression of the syndrome restricted to the limbs and kidney, including fusion and disorganization of metacarpal and phalangeal bones, radioulnar synostosis, and typical syndactyly and oligodactyly of hands and feet, as well as severe kidney hypoplasia, single left kidney with hypertrophy.Genetic analysis of the whole family by sequencing revealed a novel missense mutation c.1117C>T (p.R373W) in the LRP4 gene.The mutation which is located in extracellular domains of LRP4 within highly conserved regions may abolish its antagonistic effect on LRP6/LRP5-mediated activation of WNT signaling during limb and kidney development.lrp4-knockdown in zebrafish embryos partially phenocopies the human disorder: impairing caudal fin and kidney development.Our findings demonstrate LRP4 plays a critical role in distal limb and kidney development during vertebrate embryogenesis.