WDR81

This protein functions as a negative regulator of PI3 kinase activity on endosomal membranes and is required for endosome fusion, recycling, and early-to-late endosome transport, as well as aggrephagy of ubiquitinated protein aggregates. Biallelic mutations cause autosomal recessive cerebellar ataxia with impaired intellectual development and dysquilibrium syndrome (CAMRQ2) and congenital hydrocephalus with brain anomalies through loss-of-function mechanisms that disrupt endolysosomal trafficking. The gene shows moderate constraint against loss-of-function variants, consistent with recessive inheritance requiring biallelic mutations for disease manifestation.