Bi-allelic variants in FSD1L cause a neurodevelopmental disorder overlapping with L1 syndrome

Disruption of the complex processes underlying central nervous system development leads to a broad spectrum of brain malformations and neurodevelopmental disorders, often with a genetic cause. Here, we report bi-allelic pathogenic variants in fibronectin type III and SPRY domain-containing 1-like (FSD1L), encoding a protein of unknown function, in eleven individuals, including five fetuses from six unrelated families. The phenotype ranges from severe hydrocephalus, corpus callosum agenesis, and absent pyramid decussation to a neurodevelopmental syndrome characterized by severe intellectual disability, spastic tetraparesis, reduced vision, and epilepsy, associated with corpus callosum agenesis/hypoplasia, mild ventricular dilation, optic nerve hypoplasia, and white matter reduction. This phenotype closely resembles that observed in L1 syndrome, caused by pathogenic variants in L1CAM, encoding a neural adhesion molecule. The knockdown of Fsd1l in mouse embryos recapitulated the ventricular dilation observed in affected fetuses. Immunohistochemical studies in human control fetuses revealed that FSD1L localized to neurons with commissural fate and projection neurons during human development. Induced pluripotent stem cell (iPSC)-derived neural progenitor cells from affected individuals failed to differentiate into premature neurons and to properly form neurospheres while undergoing increased cell death. In neural progenitors, FSD1L localized with microtubules of the mitotic spindle during M phase and to the transition zone and along the axoneme of the primary cilium during interphase. In line with this, fibroblasts from affected individuals exhibited marked alterations of the mitotic spindle and reduced ciliogenesis and ciliary length compared to control cells. Our findings define FSD1L as a microtubule-associated protein implicated in neuronal differentiation, axon guidance, and fasciculation.