CC2D1A causes ciliopathy, intellectual disability, heterotaxy, renal dysplasia, and abnormal CSF flow

Abstract

Intellectual and developmental disabilities result from abnormal nervous system development. Over a 1,000 genes have been associated with intellectual and developmental disabilities, driving continued efforts toward dissecting variant functionality to enhance our understanding of the disease mechanism. This report identified two novel variants inCC2D1Ain a cohort of four patients from two unrelated families. We used multiple model systems for functional analysis, includingXenopus,Drosophila, and patient-derived fibroblasts. Our experiments revealed thatcc2d1ais expressed explicitly in a spectrum of ciliated tissues, including the left–right organizer, epidermis, pronephric duct, nephrostomes, and ventricular zone of the brain. In line with this expression pattern, loss ofcc2d1aled to cardiac heterotaxy, cystic kidneys, and abnormal CSF circulation via defective ciliogenesis. Interestingly, when we analyzed brain development, mutant tadpoles showed abnormal CSF circulation only in the midbrain region, suggesting abnormallocalCSF flow. Furthermore, our analysis of the patient-derived fibroblasts confirmed defective ciliogenesis, further supporting our observations. In summary, we revealed novel insight into the role ofCC2D1Aby establishing its new critical role in ciliogenesis and CSF circulation.