Phenotypic heterogeneity and genotypic spectrum of inborn errors of immunity identified through whole exome sequencing in a Thai patient cohort

Abstract

Background Inborn errors of immunity (IEI) comprise more than 400 rare diseases with potential life‐threatening conditions. Clinical manifestations and genetic defects are heterogeneous and diverse among populations. Here, we aimed to characterize the clinical, immunologic, and genetic features of Thai pediatric patients with IEI. The use of whole‐exome sequencing (WES) in diagnosis and clinical decision making was also assessed. Methods Thirty six unrelated patients with clinical and laboratory findings consistent with IEI were recruited from January 2010 to December 2020. WES was performed to identify the underlying genetic defects. Results The median age of disease onset was 4 months (range: 1 month to 13 years), and 24 were male (66.7%). Recurrent sinopulmonary tract infection was the most common clinical presentation followed by septicemia and severe pneumonia. Using WES, we successfully identified the underlying genetic defects in 18 patients (50%). Of the 20 variants identified, six have not been previously described (30%). According to the International Union of Immunological Societies (IUIS), 38.9% of these detected cases (7/18) were found to harbor variants associated with genes in combined immunodeficiencies with associated or syndromic features (Class II). Conclusion The diagnostic yield of WES in this patient cohort was 50%. Six novel genetic variants in IEI genes were identified. The clinical usefulness of WES in IEI was demonstrated, emphasizing it as an effective diagnostic strategy in these genetically heterogeneous disorders.

A Next Generation Sequencing (NGS)-based approach to diagnosing Algerian patients with suspected Inborn Errors of Immunity (IEIs)

“…Because of the incredible phenotypic overlap across many of these conditions, broad NGS-based approaches are increasingly employed for first-line molecular genetic testing [3]. This may be in the form of TGPs, encompassing genes associated with specific clinical diagnoses, or more broadly as WES or whole genome sequencing (WGS), which may improve diagnostic yields for IEIs and reduce overall costs [4][5][6][7][8][9][10], but whose widespread clinical use remains limited by issues of accessibility and cost. Thus, in many settings, TGPs still remain the preferred first-line approach for IEIrelated molecular diagnostic testing and are particularly useful for specific clinical presentations associated with a limited and stable repertoire of monogenic etiologies, or where somatic mosaicism or recurrent mutations may be involved.…”