Résumé
Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous developmental disorder with multiple defects. Through whole exome sequencing, we identified three unrelated individuals with the same de novo rare variant in DCAF15 (NM_138353.3:c.1409C>T; p.Ser470Phe). Clinical features included severe developmental delay, microcephaly, congenital heart defect, and craniofacial features consistent with CdLS. In one case, termination of pregnancy was performed following a diagnosis of fetal malformation syndrome. DCAF15 (DDB1 and CUL4 Associated Factor 15) is the substrate-recognition component of the DCX complex, a cullin-4-RING E3 ubiquitin-protein ligase that mediates ubiquitination of target proteins, including proteins of the cohesion family. The p.Ser470Phe variant is located within a highly conserved protein fold that is predicted to recognize these target proteins. Protein analysis in primary cells from two affected individuals demonstrated DCAF15/Cullin-4 (E3 Ubiquitin Ligase) influenced ubiquitination and accumulation of SMC3, suggesting a gain-of-function mechanism and thus, providing a functional link with CdL syndrome. EpiSign analysis demonstrated DNA methylation signature consistent with CdLS. Functional validation in the zebrafish model showed accumulated smc3 and phenotypically mimicked the patients’ presentations of stunted growth, altered head width, visual and auditory impairments, and structural heart defects. As well, the crispants displayed neurological presentations including reduced cerebellar neurons and shorter spinal motor neuron axons. Remarkably, induslam treatment rescued the upregulated SMC3 in both the cellular and zebrafish models. In summary, these findings broaden the CdLS genetic heterogeneity, describe a novel DCAF15 variant, and provide insights into the disease mechanism that can serve as a potential treatment.