Biallelic novel CCDC186 loss-of-function variant disrupting the gene function causes neurodevelopmental phenotype and review of the literature

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dc.contributor.authorGezdirici, Alper
dc.contributor.authorTurk, Sultan Buse
dc.contributor.authorEsen, Tuna Eren
dc.contributor.authorYavas, Cuneyd
dc.contributor.authorAkbulut, Ekrem
dc.contributor.authorYilmaz, Halil Ibrahim
dc.contributor.authorDogan, Mustafa
dc.date.accessioned2026-06-19T06:40:52Z
dc.date.available2026-06-19T06:40:52Z
dc.date.issued2025
dc.departmentMalatya Turgut Özal Üniversitesi
dc.description.abstractBackground: 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.
dc.identifier.doi10.1016/j.braindev.2025.104393
dc.identifier.issn0387-7604
dc.identifier.issn1872-7131
dc.identifier.issue4
dc.identifier.orcid0000-0002-7526-9835
dc.identifier.orcid0000-0001-8714-4768
dc.identifier.orcid0009-0000-0342-9900
dc.identifier.pmid40633195
dc.identifier.scopus2-s2.0-105009846058
dc.identifier.scopusqualityQ2
dc.identifier.urihttps://doi.org/10.1016/j.braindev.2025.104393
dc.identifier.urihttps://hdl.handle.net/20.500.12899/5939
dc.identifier.volume47
dc.identifier.wosWOS:001530801900001
dc.identifier.wosqualityQ3
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherElsevier
dc.relation.ispartofBrain & Development
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.snmzKA_WOS_20260612
dc.subjectCcdc186
dc.subjectLoss-Of-Function
dc.subjectMicrocephaly
dc.subjectEpilepsy
dc.subjectNeurodevelopmental Delay
dc.titleBiallelic novel CCDC186 loss-of-function variant disrupting the gene function causes neurodevelopmental phenotype and review of the literature
dc.typeArticle

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