Clinical, immunological and genetic evaluation of patients with primary immunodeficiency, with identification of novel variants

Background/Aim: Primary Immunodeficiency defines a group of disorders that occur due to congenital, developmental and/or maturational disruptions of immune system elements; resulting in autoimmunity, immune dysregulation, and chronic/recurrent infections. Diseases in this group occur as a result of inherited gene defects that damage the production or structure of the components involved in the functioning of the immune system. The significance of genetic tests has been increasingly understood in regard with many aspects of primary immunodeficiencies; including making a definitive diagnosis, overseeing the prognosis, choosing the treatment procedure and determining the subtype and finally, genetics has become an indispensable mainstay in the evaluation of this group of patients in recent years. In this study, by concurrently evaluating the phenotypic features and the genotypic backgrounds of all patients we aimed to gain an idea about the changes seen in the Turkish population, to access incidental data, and also to improve our insight into the genotype-phenotype correlation by reviewing the previously undefined variants with their clinical data. Methods: Patients that have applied to Necmettin Erbakan University Meram Medical Faculty Hospital, Department of Medical Genetics between 2017 and 2021 with pre-diagnosis of immunodeficiency and/or related complaints were included. After pre-evaluation step consisting of history and physical examination, patient DNAs were isolated using a previously defined DNA isolation method from at least 3cc blood in an EDTA tubes. After the isolation, NGS analysis was performed with the "Primary Immunodeficiency - Celemics Target Capture Kit" containing 64 genes that have been shown to be related with immunodeficiencies. The phenotypic and genotypic data of the patients were evaluated and were classified according to ACMG (American College of Medical Genetics) guidelines based on database searches and in-silico analyzes simulating protein function. Results: As multiple gene alterations were reported in some samples, a total of 354 variants were reported in 224 patients, falling into the classes of likely benign, variants of unknown VI significance, likely pathogenic, and pathogenic. The most frequently reported gene was DOCK8 (36 patients, 10.2%), followed by LRBA (25 patients, 7.2%), ATM (24 patients, 6.9%), TNFRSF13B (20 patients, 5.8%) and PRF1 (17 patients, 4.9%). Conclusion: A comprehensive evaluation of the changes in the genes associated with immune system disorders was made, and new genotype phenotype associations were established by discussing the variants whose pathogenicity has not been clarified until now or have never been reported in the literature before. The data obtained can be a guide for future research and approach to patients in this field, in addition to its contribution to the literature.