# Genetic analysis of children with suspected immunodeficiency: mimickers of inborn errors of immunity

## TL;DR

This study shows that genetic testing in children with suspected immune disorders can reveal both immune-related and unrelated genetic conditions, improving accurate diagnosis and management.

## Contribution

The study introduces the importance of identifying non-IEI-related genetic variants in patients with suspected immunodeficiency using NGS.

## Key findings

- NGS identified IEI-related pathogenic variants in 35.4% of patients.
- Non-IEI-related pathogenic variants were found in 15.2% of patients.
- A multidisciplinary approach improved diagnosis and management of mixed or atypical IEI phenotypes.

## Abstract

Inborn errors of immunity (IEI) comprise a heterogeneous group of disorders with diverse clinical manifestations. In this study, we aimed to evaluate genetic findings in patients with suspected IEI and to assess the contribution of next-generation sequencing (NGS) in identifying both IEI-related and non-IEI-related genetic variants. Between January 2020 and January 2025, 91 pediatric patients (0–18 years) referred for suspected IEI were retrospectively analyzed. Demographic data, clinical features, immunological profiles, and genetic results were reviewed, including single-gene sequencing, fluorescence in situ hybridization (FISH), targeted gene panels (TGP), and whole-exome sequencing (WES). Patients analyzed by NGS were classified into three categories according to detected variants: IEI-related, non-IEI-related, and undetected disease-causing variant. A total of 79 patients underwent NGS-based genetic testing. The mean age was 4.37 ± 5.09 years. WES was performed in 40 patients (50.6%) and TGP in 39 (49.4%). Pathogenic variants linked to IEI-related were detected in 28 patients (35.4%), whereas non-IEI-related pathogenic variants were identified in 12 (15.2%). The remaining 39 patients (49.4%) had undetected disease-causing variants. The diagnoses of patients carrying pathogenic variants unrelated to IEI included primary ciliary dyskinesia, Ellis–van Creveld syndrome, desmoglein-1 deficiency, and others.

Conclusion: Our study highlights the importance of genetic testing in the differential diagnosis of IEI and provides evidence supporting its role in identifying mixed IEI phenotypes. Comprehensive interpretation of genetic results within a multidisciplinary clinical framework is essential for accurate diagnosis, appropriate management, and effective genetic counseling.

What is Known:

• Inborn errors of immunity are rare, genetically heterogeneous disorders with overlapping phenotypes, often causing delayed diagnosis and necessitating next-generation sequencing.

• Recent multicenter studies show that whole-exome sequencing has increased diagnostic yield to over 40-50% and improved clinical classification and management.

What is New:

• Comprehensive genetic testing revealed clinically significant non–IEI-related variants in 15.2% of patients with mixed or atypical IEI phenotypes.

• A multidisciplinary approach broadened the diagnostic perspective beyond classical IEI, enabling more accurate and individualized patient management.