Gezdirici, AlperTurk, Sultan BuseEsen, Tuna ErenYavas, CuneydAkbulut, EkremYilmaz, Halil IbrahimDogan, Mustafa2026-06-192026-06-1920250387-76041872-7131https://doi.org/10.1016/j.braindev.2025.104393https://hdl.handle.net/20.500.12899/5939Background: Coiled-coil domain-containing protein 186 (CCDC186) is essential for the transport of secretory dense-core vesicles (DCVs), specialized organelles responsible for storing and releasing neurotransmitters and other modulatory molecules in neurons and endocrine cells, thereby playing a crucial role in physiological processes such as synaptic plasticity, neurotransmission, and hormonal regulation. Resent reports have suggested that biallelic loss-of-function (LOF) variants in CCDC186 may be associated with neurodevelopmental disorders and a range of systemic manifestations. Methods: Whole exome sequencing (WES) was performed, and co-segregation analysis of the family was conducted using sanger sequencing. Additionally, five patients with CCDC186-associated phenotypes previously described in the literature were evaluated. Followed by cDNA synthesis and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to analyze gene expression levels. Bioinformatics tools, including RoseTTAFold for protein modeling and STRING for protein-protein interaction networks, were employed to assess the structural and functional consequences of the mutation. Results: We identified a homozygous NM_018017.4:c.535C>T (p.Arg179Ter) nonsense variant in the CCDC186 gene. This variant was associated with a marked downregulation of CCDC186 expression in the proband, with moderate reductions observed in heterozygous family members, suggesting dysregulated gene expression resulting from the mutation. Protein modeling indicated structural alterations, including a shift from intrinsically disordered regions to helix-loop-helix motifs in the mutant protein, as well as reduced binding probabilities for most interacting partners. Conclusion: In this study, we presented the comprehensive clinical and genetic profiles of a Turkish child with a novel CCDC186 variant, along with five previously reported patients from the literature. Our findings support that the homozygous LOF variants of the CCDC186 gene are associated with a novel neurodevelopmental phenotype.eninfo:eu-repo/semantics/closedAccessCcdc186Loss-Of-FunctionMicrocephalyEpilepsyNeurodevelopmental DelayArticle10.1016/j.braindev.2025.104393474406331952-s2.0-105009846058Q2WOS:001530801900001Q30000-0002-7526-98350000-0001-8714-47680009-0000-0342-9900