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Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders
Scopus
Toplam 261 atıf DOI
Background Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Methods Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.
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Genetic analysis of children with suspected immunodeficiency: mimickers of inborn errors of immunity
Scopus
Havuzumuzda Open Access
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.
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Kurumlar (1)
Selçuk Tip Fakültesi
Konya, Turkey