Genomic sequencing can reveal potentially life-threatening clinically actionable secondary findings in healthy individuals. Little is known about the spectrum and frequency of secondary findings in healthy people in Russia. Here, we analyzed whole-genome sequences of 42,826 healthy volunteers from urban populations across Russia, focusing on known pathogenic and likely pathogenic variants of 81 genes associated with treatable or preventable monogenic diseases listed in the American College of Medical Genetics and Genomics’ Secondary Findings recommendations (ACMG SF v3.2). Based on the ClinVar 20250421 version, secondary findings were detected in 1186 (2.76%) participants. Cancer phenotypes were the most common category of secondary findings present in 565 (1.32%) participants, followed by cardiovascular phenotypes (454 individuals, 1.05%). Genes harboring the most frequent variants were BRCA1 (151 variants), BRCA2 (100), RYR1 (93), and LDLR (71). In addition, we found 238 potential loss-of-function variants in dominant ACMG SF v3.2 list genes in 280 (0.65%) participants, which, if confirmed by orthogonal methods, could increase the frequency of secondary findings to 3.41%. A study of such depth and scale was performed for the first time in the Russian population.

The study purpose was to assess the diagnostic value of whole-genome sequencing (WGS) in identifying candidate genetic variants in patients with inherited retinal diseases (IRDs). We investigated 107 unrelated Russian patients with retinal diseases who carried single pathogenic variants in any of nine common autosomal recessive IRD genes (ABCA4, USH2A, EYS, CRB1, RPE65, CNGB3, CNGA3, CEP290, and GUCY2D). WGS was performed for all patients; candidate splice variants were functionally validated using minigene assays. The total diagnostic yield was 40.2% (43/107). In 25.2% of cases (27/107), the diagnosis was established by identifying a second variant in one of the following candidate genes: EYS (n = 9), USH2A (n = 8), ABCA4 (n = 5), CNGB3 (n = 3), CRB1 and CEP290 (n = 1 each). In 15.0% of cases (16/107), the diagnosis was reclassified by variants in alternative IRD genes (autosomal dominant, X-linked, mitochondrial, or syndromic). The majority of second variants detected in AR cases were CNVs (55.5%, 15 patients), followed by non-coding variants (26.0%, seven), structural rearrangements (14.8%, four) and exonic point variant (3.7%, one). Two recurrent CNVs were observed: a gross deletion of exons 22–24 in USH2A (n = 4) and a deletion partially affecting exon 19 of EYS (n = 4). Structural variants were mostly represented by delINV rearrangements (n = 5). Minigene assays confirmed that three novel deep intronic variants (in CHM, EYS, and CEP290) and one non-canonical splice-acceptor variant in USH2A which disrupt splicing, causes pseudoexon inclusion with premature termination or in-frame exon skipping respectively. Thus, WGS improves the diagnostic yield in IRDs by detecting variants missed by targeted sequencing, supporting its clinical utility in ophthalmologic practice.

Identifying genetic cause(s) is a key step for management and treatment of patients with inborn errors of immunity (IEI). Here, in an observational cross-sectional genomic study, we analyzed whole-genome sequencing (WGS) data of 72 IEI patients from Saint Petersburg and Northwestern Russia: 42 patients with common variable immunodeficiency (CVID)-like phenotypes, 6 patients with clinically diagnosed X-linked agammaglobulinemia (XLA or Bruton’s disease), and 24 patients with other forms of IEI. Causative pathogenic and likely pathogenic variants in BTK, CYBB, CHD7, AIRE, ATM, SBDS, NFKB1, and CTLA4 genes were identified in 14 (19%) patients. Variants of uncertain significance that could be linked to observed clinical phenotypes were detected in 6 patients. These included a BTK variant in a patient with Bruton’s disease, variants in SH2D1A, SOCS1, and IKBKB in patients with CVID, and variants in CARD11 and CD40LG in patients with other forms of IEI. Additional rare variants that were mostly unique to individual patients were found in multiple IEI genes from the International Union of Immunological Societies (IUIS) Expert Committee 2024 list. In the CVID-like subcohort, pathway-level analysis of these rare variants revealed patterns associated with clinical manifestations. Taken together, our results expand the genetic characterization of an understudied regional IEI cohort, particularly of patients with CVID-like phenotypes, and identify genetic factors that are implicated in or may contribute to the disease.