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    Biallelic novel CCDC186 loss-of-function variant disrupting the gene function causes neurodevelopmental phenotype and review of the literature
    (Elsevier, 2025) Gezdirici, Alper; Turk, Sultan Buse; Esen, Tuna Eren; Yavas, Cuneyd; Akbulut, Ekrem; Yilmaz, Halil Ibrahim; Dogan, Mustafa
    Background: 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.
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    The role of ATP9A (c.1091G > C; p.(Arg364Thr)) variant in cognitive impairment: diagnostic insight from whole exome sequencing
    (Springer, 2026) Yavas, Cuneyd; Abuaisha, Asmaa; Nekay, Emir; Gezdirici, Alper; Yilmaz, Halil Ibrahim; Akbulut, Ekrem; Arican, Pinar
    Background The ATP9A gene encodes a P4-type ATPase involved in phospholipid translocation, essential for vesicular trafficking and neuronal development. Pathogenic ATP9A variants cause autosomal recessive neurodevelopmental disorders characterized by intellectual disability and microcephaly, yet the impact of missense variants remains poorly understood. Methods A 7-year-old female patient with cognitive impairment, microcephaly, and developmental delay was admitted to Ba & scedil;ak & scedil;ehir & Ccedil;am and Sakura City Hospital. Whole exome sequencing (WES) using Illumina technology identified a novel homozygous ATP9A variant, confirmed by Sanger sequencing and segregation analysis. In silico tools (RosettaFold, DynaMut, mCSM, SDM, DUET, AggreScan3D) assessed its structural impact. Quantitative real-time polymerase chain reaction (RT-qPCR) was conducted to evaluate the relative expression levels of ATP9A. Results WES revealed a homozygous missense variant, ATP9A: NM_006045.3:c.1091G > C:p.(Arg364Thr), classified as variant of uncertain significance based on ACMG guidelines (PP2, PM2, PM3). Protein modeling demonstrated reduced stability (Delta Delta G = - 1.51 to - 0.26 kcal/mol), increased flexibility, and a 2.4-fold decrease in solvent accessibility. The variant disrupted polar and hydrophobic interactions within the P-type ATPase IV domain, thereby increasing aggregation propensity. Expression analysis revealed elevated ATP9A mRNA levels, suggesting a compensatory cellular response. Conclusion This novel ATP9A variant broadens the mutational spectrum of ATP9A-related neurodevelopmental disorders. Structural destabilization of the p.(Arg364Thr) protein may contribute to the patient's cognitive impairment and microcephaly, warranting further functional studies.