Phenotypic Expansion and Molecular Implications in Recessive FUZ -Related Ciliopathy

FUZ, a component of the CPLANE (ciliogenesis and planar polarity effector) complex, regulates primary ciliogenesis. Five patients of various types of skeletal dysplasia with biallelic FUZ variants have been reported to date, yet the gene-disease relationship has not been established. Here, we report a patient with ciliopathy with a novel homozygous missense variant in FUZ. This patient shares phenotypes with all the previously reported patients and presents with novel phenotypes: aorto-pulmonary window (AP window) and Hirschsprung disease. These phenotypes can be explained by the inhibition of neural crest cell migration due to abnormal Sonic hedgehog (Shh) signaling caused by primary cilia dysfunction. In silico three-dimensional structural analysis predicted that the variant alters interactions between FUZ and CPLANE2 (RSG1), potentially disrupting ciliogenesis. This report provides additional evidence for FUZ as a causative gene for ciliopathy, offering novel insights into the phenotype spectrum and molecular mechanisms of FUZ-related ciliopathy.