Bi-allelic variants inWDR47lead to neuronal loss causing a rare neurodevelopmental syndrome with corpus callosum dysgenesis in humans

Abstract

ABSTRACTThe corpus callosum (CC) is the largest interhemispheric connection that is largely formed by the axons of layer 2/3 callosal projection neurons (CPNs) through a series of tightly regulated cellular events, including neuronal specification, migration, axon extension and branching. Defects in any of those steps may prevent the proper development of the corpus callosum resulting in a spectrum of disorders collectively referred to as corpus callosum dysgenesis (CCD). Here, we report four unrelated families carrying bi-allelic variants inWDR47presenting with CCD together with other neuroanatomical phenotypes such as microcephaly, cerebellar abnormalities and hydrocephalus. Using a combination ofin vitroandin vivomouse models and complementation assays, we show that independently from its previously identified functions in neuronal migration and axonal extension, WDR47 is required for survival of callosal neurons by contributing to the maintenance of mitochondrial and microtubule homeostasis. We further provide evidence that severity of the CCD phenotype is determined by the degree of the loss of function caused by the human variants. Taken together, we identifyWDR47as a causative gene of a new neurodevelopmental syndrome characterized by corpus callosum abnormalities and other neuroanatomical malformations.