Genetic landscape of Romanian children with inborn errors of immunity via gene panels, exome, and genome sequencing

Inborn errors of immunity (IEI) are monogenic disorders with a wide spectrum of clinical phenotypes including immune dysregulation, autoimmunity, autoinflammation, and malignancy. IEI may have life-threatening consequences, thus precise and timely genetic diagnosis is crucial for improved access to treatment, genetic counselling and prevention. We aimed to investigate the genotypic findings in a cohort of children with IEI from Romania, in order to understand the diagnostic yield of genetic testing, genetic characterization of IEI and impact of genetic diagnosis. Clinical and genetic investigations were performed in 92 children (50% boys) with IEI phenotype, evaluated between 2018 and 2024, in a tertiary reference genetic center in Timisoara, Romania. Sanger sequencing, next generation sequencing panels with genes associated with IEI (1-474 genes), WES and WGS were used. Disease-causing variants for IEI (pathogenic/likely pathogenic) were identified in 37/92 (40.2%) participants, in 25 genes. 14/92 (15.2%) participants had relevant variants of uncertain significance. Median age at genetic testing was 4.38 (IQR 2-12.8) years. 15/37 (40.5%) of patients with Disease-causing variants had a family history of IEI. NGS gene panels were used in 43/92 (46.7%) patients, WES in 29 (31.5%), while WGS in 20 (21.7%). Twelve patients had more than one genetic test. Most frequent genes with Disease-causing variants identified were: JAGN1(5 patients) and AIRE(3). A great variety of genes were identified as causative for IEI. Considering the highly variable and unspecific phenotype, together with no family history in most cases, prioritizing genetic investigations offers the best option for timely diagnosis and treatment.