WDR81 mutations cause microlissencephaly and microcephaly and impair mitotic progression in neural progenitors

Objective: Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. Methods: We performed trio-based whole exome sequencing in 7 subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. Results: We identified compound heterozygous mutations in WDR81, a gene previously associated with cerebral ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe MLIS with or without pontocerebellar hypoplasia to moderate microcephaly with cerebellar hypoplasia. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase. Similarly, in vivo, we showed that knockdown of the WDR81 ortholog in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations which includes cerebellar atrophy, microcephaly and microlissencephaly. Conclusion: Our results demonstrate that WDR81 has a crucial role in centrosome function and mitosis, a role conserved between Drosophila and humans.