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

Intellectual disability (ID) results from abnormal nervous system development. Over a thousand genes have been associated with ID, driving continued efforts toward dissecting variant functionality to enhance our understanding of the disease mechanism. This report identified two novel variants in CC2D1A in a cohort of four patients in two unrelated families. We utilized multiple model systems for functional analysis, including Xenopus, Drosophila, and patient-derived fibroblasts. Our experiments revealed that cc2d1a is 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 of cc2d1a led to cardiac heterotaxy, cystic kidneys, and abnormal CSF circulation via defective ciliogenesis. Interestingly, when we analyzed brain development with optical coherence tomography imaging, mutant tadpoles showed abnormal cilia-driven cerebrospinal fluid circulation only in the midbrain region, suggesting abnormal local CSF 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 of CC2D1A in normal development and its associated expanding diseases, including ID, autism, congenital heart disease, and kidney disease, by establishing its new critical role in ciliogenesis and cilia-driven CSF circulation.