Biallelic UNC5C variants cause a recessive neurodevelopmental disorder with brain anomalies

ABSTRACT: Precise axon guidance is fundamental to neural circuit formation, yet the full spectrum of neurodevelopmental disorders arising from disruptions in this process remains undefined. Here, we describe a multi-ethnic cohort of eight patients from five independent families presenting with a neurodevelopmental disorder characterized by structural brain anomalies, distal limb contractures, developmental delay, intellectual disability, and additional variable features. All affected individuals carry biallelic deleterious variants in UNC5C, a gene encoding a conserved netrin receptor essential for axon guidance and neuronal migration. To investigate the functional consequences of these variants, we performed structural analyses, which indicated that the identified variants disrupt key functional domains, including the immunoglobulin-like (Ig), thrombospondin-1 type repeats (TSP), ZU5, UPA, and death domains. We then introduced disease-associated mutations into conserved residues of the Caenorhabditis elegans unc-5 orthologue using CRISPR/Cas9 genome editing and assessed phenotypic outcomes in vivo. Cell-type-specific rescue experiments revealed the observed motor defects are primarily neurogenic in origin. Consistent with the clinical features observed in patients, C. elegans carrying the corresponding human mutations exhibited defects in axon guidance, locomotion, and behaviour, supporting disruption of UNC-5–mediated signalling pathways. Together, our findings establish biallelic pathogenic variants in UNC5C as the cause of a previously unrecognized autosomal recessive neurodevelopmental disorder with structural brain anomalies and distal limb contractures. Our combined approach of human genetics and in vivo modelling defines a critical role for UNC5C in human neurodevelopment and expands the spectrum of disorders arising from disrupted axon guidance machinery.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE326863 | GEO | 2026/04/10

REPOSITORIES: GEO