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Objective: Inborn errors of immunity (IEIs) comprise a genetically heterogeneous group of disorders predisposing individuals to recurrent and severe infections, autoimmunity, and immune dysregulation. Next-generation sequencing (NGS) has greatly improved diagnostic efficiency by allowing simultaneous analysis of multiple genes. This study aimed to evaluate the molecular diagnostic yield and characterize the variant spectrum in patients with suspected IEIs using a targeted NGS panel. Methods: A total of 101 pediatric patients clinically diagnosed with IEIs and referred to the Pediatric Genetics Department Ümraniye Training and Research Hospital between 2018 and 2021 were included in the study. Genetic analysis was performed using a targeted NGS panel encompassing 260 genes associated with IEIs. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) and Clinical Genome (ClinGen) Sequence Variant Interpretation (SVI) guidelines. Single-nucleotide variants (SNVs) were confirmed by Sanger sequencing, and copy number variants (CNVs) were validated using array-based comparative genomic hybridization (array-CGH). Results: Pathogenic or likely pathogenic (P/LP) variants were identified in 25 of 101 patients (24.7%), yielding 26 distinct variants across 21 genes, including one patient with two variants in a compound heterozygous state. Among these, 18 were homozygous, 3 heterozygous, 3 hemizygous, and 1 compound heterozygous. The most frequently affected genes were RAG1, DCLRE1C, SPINK5, and STAT1. Three novel variants were identified, expanding the known mutational spectrum of IEIs. In addition, several variants initially identified in this cohort were later reported by our group, highlighting the contribution of our study to the expanding genetic spectrum of IEIs in Türkiye. Most variants exhibited autosomal recessive inheritance, consistent with the high consanguinity rate in the study population. Conclusion: In our IEI cohort, targeted NGS achieved a 24.7% molecular diagnostic yield and successfully identified both known and novel pathogenic variants across a broad spectrum of genes. These findings highlight the diagnostic value of targeted NGS in genetically and clinically heterogeneous conditions such as IEIs and underscore the importance of population-specific variant databases for improving variant interpretation and optimizing patient care.