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    Developmental and epileptic encephalopathy 82 (DEE82) with novel compound heterozygous mutations of GOT2 gene
    (W B Saunders Co Ltd, 2024) Capan, Ozlem Yalcin; Turkdogan, Dilsad; Atalay, Sertac; Caglayan, Hande S.
    Purpose: Developmental and Epileptic Encephalopathies (DEEs) are rare neurological disorders characterized by early-onset medically resistant epileptic seizures, structural brain malformations, and severe developmental delays. These disorders can arise from mutations in genes involved in vital metabolic pathways, including those within the brain. Recent studies have implicated defects in the mitochondrial malate aspartate shuttle (MAS) as potential contributors to the clinical manifestation of infantile epileptic encephalopathy. Although rare, mutations in MDH1, MDH2, AGC1, or GOT2 genes have been reported in patients exhibiting neurological symptoms such as global developmental delay, epilepsy, and progressive microcephaly. Method: In this study, we employed exome data analysis of a patient diagnosed with DEE, focusing on the screening of 1896 epilepsy-related genes listed in the HPO and ClinVar databases. Sanger sequencing was subsequently conducted to validate and assess the inheritance pattern of the identified variants within the family. The evolutionary conservation scores of the mutated residues were evaluated using the ConSurf Database. Furthermore, the impacts of the causative variations on protein stability were analyzed through I-Mutant and MuPro bioinformatic tools. Structural comparisons between wild-type and mutant proteins were performed using PyMOL, and the physicochemical effects of the mutations were assessed using Project Hope. Results: Exome data analysis unveiled the presence of novel compound heterozygous mutations in the GOT2 gene coding for mitochondrial glutamate aspartate transaminase. Sanger sequencing confirmed the paternal inheritance of the p.Asp257Asn mutation and the maternal inheritance of the p.Arg262Cys mutation. The affected individual exhibited plasma metabolic disturbances, including hyperhomocysteinemia, hyperlactatemia, and reduced levels of methionine and arginine. Detailed bioinformatic analysis indicated that the mutations were located within evolutionarily conserved domains of the enzyme, resulting in disruptions to protein stability and structure. Conclusion: Herein, we describe a case with DEE82 (MIM: # 618721) with pathologic novel biallelic mutations in the GOT2 gene. Early genetic diagnosis of metabolic epilepsies is crucial for long-term neurodevelopmental improvements and seizure control as targeted treatments can be administered based on the affected metabolic pathways.
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    Exome data of developmental and epileptic encephalopathy patients reveals de novo and inherited pathologic variants in epilepsy-associated genes
    (W B Saunders Co Ltd, 2024) Capan, Ozlem Yalcin; Yapici, Zuhal; Ozbil, Mehmet; Caglayan, Hande S.
    Purpose: In Developmental and Epileptic Encephalopathies (DEEs), identifying the precise genetic factors guides the clinicians to apply the most appropriate treatment for the patient. Due to high locus heterogeneity, WES analysis is a promising approach for the genetic diagnosis of DEE. Therefore, the aim of the present study is to evaluate the utility of WES in the diagnosis and treatment of DEE patients. Methods: The exome data of 29 DEE patients were filtrated for destructive and missense mutations in 1896 epilepsy-related genes to detect the causative variants and examine the genotype-phenotype correlations. We performed Sanger sequencing with the available DNA samples to follow the co-segregation of the variants with the disease phenotype in the families. Also, the structural effects of p.Asn1053Ser, p.Pro120Ser and p. Glu1868Gly mutations on KCNMA1, NPC2, and SCN2A proteins, respectively, were evaluated by molecular dynamics (MD) and molecular docking simulations. Results: Out of 29, nine patients (31%) harbor pathological (P) or likely pathological (LP) mutations in SCN2A, KCNQ2, ATP1A2, KCNMA1, and MECP2 genes, and three patients have VUS variants (10%) in SCN1A and SCN2A genes. Sanger sequencing results indicated that three of the patients have de novo mutations while eight of them carry paternally and/or maternally inherited causative variants. MD and molecular docking simulations supported the destructive effects of the mutations on KCNMA1, NPC2, and SCN2A protein structures. Conclusion: Herein we demonstrated the effectiveness of WES for DEE with high locus heterogeneity. Identification of the genetic etiology guided the clinicians to adjust the proper treatment for the patients.
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    Navigating Uncertainty: Assessing Variants of Uncertain Significance in the CDKL5 Gene for Developmental and Epileptic Encephalopathy Using In Silico Prediction Tools and Computational Analysis
    (Springernature, 2025) Capan, Ozlem Yalcin
    Mutations in the CDKL5 gene are associated with developmental and epileptic encephalopathy (DEE), a severe disorder characterized by developmental delay and epileptic activity. In genetic analyses of DEEs, variants classified as pathogenic confirm the diagnosis of the disease while Variants of Uncertain Significance (VUS) remain in a gray area due to insufficient evidence. This study aimed to optimize the interpretation of VUS in the CDKL5 gene by evaluating the performance of 22 in silico prediction tools using 186 known pathogenic or benign missense variants from the ClinVar database. The best-performing tools were then applied to analyze CDKL5 VUS variants, complemented by the evaluation of evolutionary conservation, structural analyses, and molecular dynamics simulations to assess their impact on protein structure and function. The results identified SNPred as the most reliable tool, achieving 100% accuracy, sensitivity, and specificity. Other high-performing tools, including ESM-1v, AlphaMissense, EVE, and ClinPred, demonstrated over 98% accuracy. Among 44 CDKL5 VUS variants evaluated, 20 were initially classified as pathogenic by these tools. However, further evaluation using stringent criteria-incorporating conservation scores, structural disruptions identified by Missense3D and PyMol, and molecular dynamics simulation results-led to the reclassification of 8 VUS variants as potentially pathogenic and the remaining 12 as variants with conflicting data. This comprehensive approach provides a robust framework for the classification of VUS in the CDKL5 gene, offering critical insights for accurate diagnosis and treatment strategies in DEE. These findings will serve as a valuable resource for clinicians and geneticists in resolving the diagnostic ambiguity associated with VUS.