Real-World Single-Center Study of Inborn Errors of Immunity in Chinese Children: Diagnostic Efficacy and Genomic Landscape Revealed by Whole-Exome Sequencing Combined with Copy Number Variant Analysis

Inborn Errors of Immunity (IEI) are genetically heterogeneous diseases with nonspecific clinical presentations, often resulting in delayed diagnosis. While whole-exome sequencing (WES) is widely used for diagnosing IEI, its real-world performance in the pediatric Chinese population remains understudied. This study retrospectively analyzed 243 children aged 0 to 15 years suspected of having IEI at a single center. All underwent WES combined with copy number variant (CNV) detection. Candidate variants were initially screened using the TGex platform and validated via Sanger sequencing. Variants were classified based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) 2015 guidelines, with only those listed as P/LP variants in genes included in the IUIS 2024 IEI list considered diagnostic. In this region with a concentrated Zhuang ethnic minority population, 77 (31.69%) of the children clinically suspected of IEI were confirmed by molecular diagnosis. Among the confirmed patients, pathogenic variants were identified in 33 genes, in addition to one recurrent copy number variant (22q11.2 deletion causing DiGeorge syndrome), which was the most frequent diagnosis. Trio-based WES was associated with a higher diagnostic yield than proband-only sequencing (60.0% vs. 29.8%, Fisher’s exact test, p = 0.021), although this comparison was based on a small number of trio cases ( n = 15) and may be subject to selection bias. CNVs accounted for 27.27% (21 cases) of all diagnoses, emphasizing the importance of integrating CNV analysis into routine WES workflows. Molecularly diagnosed cases were non-uniformly distributed across age groups: infants under six months were predominantly diagnosed with developmental immunodeficiencies, while older children showed a higher proportion of immune dysregulation and cancer-predisposing syndromes; given the cross-sectional design, these patterns should be interpreted as descriptive rather than as evidence of age-dependent phenotype evolution. Common manifestations included recurrent respiratory infections, cytopenia, and noninfectious features like congenital heart disease and neurodevelopmental delays, supporting IEI as a systemic disorder. Interestingly, 67.5% of patients displayed only 1–3 symptoms, and even those with a single symptom ( n = 40) achieved a diagnostic rate of 45.0% (18/40) in this clinically preselected cohort. Notably, diagnostic rates varied among bioinformatics analysts (more than fourfold), highlighting the potential influence of variant interpretation on diagnostic outcomes, although causality cannot be established from this analysis. IEI presents with a broad, age-stratified spectrum of clinical phenotypes, supporting age-informed diagnostic strategies. For high-risk children, WES integrated with CNV analysis—and trio sequencing when feasible—may be considered as an early molecular diagnostic strategy. Standardizing variant interpretation is essential for equitable and reproducible diagnosis. These findings provide a phenotype-driven reference for genomic diagnostics in resource-limited, ethnically diverse settings.