<scp> <i>PIK3C2A</i> </scp> ‐Related Clinical Phenotype and Cellular Charaterization Linked to Functional <scp>SHH</scp> Primary Cilia Defect

PIK3C2A is a member of the class II phosphatidylinositol-3-kinases (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and of PI(4)P into PI(3,4)P2. These second messenger lipids regulate a wide range of downstream signaling pathways involved in many physiological functions and cellular processes, including cell proliferation, growth, survival, motility, and metabolism. PIK3C2A is also involved in the regulation of primary cilia formation and maintenance and in the regulation of receptor-mediated endocytosis at the base of the cilium. PIK3C2A was recently related to a novel oculoskeletodental syndrome (OCSKD MIM#618440), combining short stature, coarse facial features, ocular, and skeletal abnormalities. We describe here the fifth family presenting a PIK3C2A-related syndrome characterized by pulverulent cataracts and deafness. Using trio exome sequencing, we identified two novel compound heterozygous variants in PIK3C2A for which functional testing was necessary to assess the effect of one of the variants. Cellular studies of patient's-derived skin fibroblasts revealed a normal PIK3C2A protein level but a defective enzyme. Ciliary and cellular phenotype studies showed in the patient's cells impaired cilia formation and function as well as a reduced proliferative capacity. This study expands the clinical and mutational spectrum of PIK3C2A-related syndrome.