In vivo modeling of novel de novo WDR44 variants associated with corpus callosal dysgenesis

Abstract

Clinical whole-exome sequencing (WES) has facilitated identifying novel candidates for rare neurodevelopmental disorders, especially for undiagnosed cases. Here we describe two patients presenting corpus callosal (CC) dysgenesis. WES revealed de novo missense mutations in WDR44 predicted to be possibly damaging in silico. To functionally validate variants’ pathogenicity, we ectopically overexpressed the variants in developing mouse embryos. Overexpression of both variants in neurons resulted in migration defect and morphological abnormality during early neurodevelopment. Ectopic expression of variants in the embryonic brain led to postnatal CC anomalies as well as reduced ipsilateral and contralateral axon branching mimicking pathologies seen in the patients. Our in vivo modeling characterized the effects of novel WDR44 variants, and this may provide opportunities for understanding the pathologies of associated neurodevelopmental disorders.