P97. Loss of CHSY1, a novel FRINGE enzyme, causes syndromic brachydactyly via increased NOTCH signaling

Abstract

We delineated a novel syndromic brachydactyly with partial duplication of proximal phalanges to 16.8 Mb over 4 chromosomes. High-throughput sequencing of all 177 candidate genes detected a disease-causing frameshift mutation in the gene CHSY1 encoding for a chondroitin synthase with a Fringe motif. CHSY1 was secreted from patient's fibroblasts where its absence triggered remarkable JAG1 synthesis and NOTCH up-regulation. Chsy1- knockdown in zebrafish embryos partially phenocopies the human disorder: increasing NOTCH output, impairing pectoral fin development and leading to dramatic retinal overgrowth. We conclude that CHSY1 is a novel FRINGE enzyme necessary to restrict NOTCH signaling during various developmental processes.