Report of a Homozygous Nonsense Variant in the <scp> <i>WDR91</i> </scp> Gene Associated With Severe Communicating Hydrocephalus, Dandy Walker Malformation, and Cerebellar Hypoplasia

The WDR81 and WDR91 genes are important for endosome conversion, fusion, recycling, and transport. Variants in the WDR81 gene have been reported in human patients with cerebellar ataxia, impaired intellectual development, and disequilibrium syndrome type 2 (CAMRQ2, MIM #610185) and in patients with congenital hydrocephalus with brain anomalies type 3 (HYC3, MIM #617967). Both phenotypes are transmitted in an autosomal recessive inheritance pattern. Loss-of-function type variants in the WDR91 gene have also been recently described in patients with brain malformations such as hydrocephalus, brain atrophy, corpus callosum agenesis, micro-lissencephaly, and cerebellar hypoplasia. However, the literature is scarce, and this association has not been cataloged in the Online Mendelian Inheritance in Man (OMIM) database. Herein, we report a novel homozygous nonsense variant in the WDR91 gene in a child with severe congenital communicating hydrocephalus, Dandy-Walker malformation (not described before in association with this gene), cerebellum hypoplasia, and facial dysmorphism. Exome sequencing (trio) revealed a novel homozygous variant c.1245_1246delAG (transcript ID NM_014149.4) in the WDR91 gene predicted to lead to premature termination variant p.(Arg415Serfs*64). The variant was confirmed on Sanger sequencing in the proband and the asymptomatic parents were shown to be heterozygous for the same variant, demonstrating autosomal recessive inheritance. A review of medical literature revealed that in mice, global Wdr91 knockout causes neonatal death, whereas brain-specific Wdr91 inactivation impairs brain development and causes marked neuronal loss in the cerebrum and cerebellum. We show that as per the Clingen guidelines for gene-disease assertion, the evidence for loss-of-function variants in the WDR91 gene leading to congenital hydrocephalus is strong and supports its inclusion in the OMIM database.