Accepted_test

Primary immunodeficiencies (PIDs) represent a heterogeneous group of inborn diseases varying by severity, manifestation age, clinical features, and genetic background. In Russia, the mutational landscape of PID patients, especially of patients with sporadic immunodeficiencies, is understudied. In this work, we conducted whole-genome sequencing (WGS) of a Russian PID cohort of 140 patients. DNA was extracted from blood samples provided by Saint-Petersburg Pasteur Institute Medical Centre and sequenced on an DNBSEQ-T7 MGI instrument. As a result, known genes enriched with rare mutations as well as several candidate genes were revealed. To reveal primarily monogenic cases of PID, we concentrated on truncating genetic changes (nonsense, frameshifts), missense mutations, and annotated splice sites in these genes. Variants with different levels of confidence were proposed based on clinical data. We concentrated on rare variants with population frequency in gnomAD and Russian population cohort of the "Biotech campus" LLC database of < 1%. Most of detected rare variants were classified as variants of uncertain significance (VUS). 11 previously known pathogenic variants and 21 new likely pathogenic variants were identified. This study highlights the potential of whole-genome sequencing to expand identification of novel variants and genes involved in PID. Identified variants can be good candidates for future functional studies to establish their role in pathogenesis.