Bi-allelic INTU variants define a ciliopathy disorder characterized by orofacial, digital, and cardiac anomalies

The primary cilium is a small organelle that plays key roles in cellular signaling. Defects in primary cilia formation, morphology, and function cause a heterogeneous group of developmental syndromes termed ciliopathies. The inturned planar cell polarity protein (INTU) gene acts in the CPLANE complex to facilitate ciliogenesis and support cilia signaling. Bi-allelic genetic variants in INTU have previously been reported in seven patients with pleiotropic disorders, but a core set of phenotypes from these patients has not been codified and functional studies into these variants have failed to fully demonstrate mechanistic perturbations caused by INTU dysfunction. Here, we report on a person with cardiac abnormalities, distinctive craniofacial features, developmental delays, tongue hamartomas, bilateral clinodactyly, and polydactyly of the left great toe. Trio whole-exome sequencing identified compound heterozygous variants in the INTU gene. Functional studies provide evidence that these INTU variants confer human disease through altered ciliogenesis and/or cilia signaling. Furthermore, we suggest that this study along with previous reports sufficiently establishes an association between a pleiotropic disorder and variants in the INTU gene to enhance clinical interpretation of INTU variants in future studies.