Auditory neuropathy spectrum disorder (ANSD) is often missed by standard hearing tests, accounting for up to 10% of hearing impairments (HI) and commonly linked to variants in 23 genes. We assessed 122 children with HI, including 102 with sensorineural hearing loss (SNHL) and 20 with ANSD. SNHL patients were genotyped for common GJB2 variants using qPCR, while ANSD patients underwent whole exome sequencing, with variants analyzed across 249 genes. Homozygous GJB2 variants were found in 54.9% of SNHL patients. In 60% of ANSD patients, variants were detected in OTOF (25%), CDH23, TMC1, COL11A1, PRPS1, TWNK, and HOMER2 genes, including eight novel variants. Transient evoked otoacoustic emissions testing revealed differences at 4000 Hz (p = 0.0084) between the ANSD and SNHL groups. The auditory steady-state response (ASSR) test showed significant differences at 500 Hz (p = 2.69 × 10⁻⁴) and 1000 Hz (p = 0.0255) compared to pure-tone audiometry (PTA) in ANSD patients. Our questionnaire shows that the parents of children with SNHL often report an improved quality of life with hearing aids or cochlear implants, while parents of children with ANSD frequently experience uncertainty about outcomes (p = 0.0026), leading to lower satisfaction.

Background: Direct oral anticoagulants (DOACs) are first-line medications for stroke prevention in non-valvular atrial fibrillation (AF). However, variability in drug response poses risks of hemorrhagic or thromboembolic events. Objectives: Although genetic influences on DOACs safety are increasingly recognized, robust evidence directly linking specific polymorphisms to bleeding risk remains limited. Design: Multi-center observational case–control study including exome-wide association analysis of 196 non-valvular AF patients treated with rivaroxaban or apixaban, comprising 97 with bleeding complications and 99 without. Methods: DOAC plasma concentrations, urinary 6-β-hydroxycortisol and cortisol levels were measured for CYP3A4 phenotyping. Sequencing was performed on the DNBSEQ G-400 platform. Single-nucleotide variant (SNV) associations with bleeding risk were assessed using logistic regression with additive, dominant, and recessive genetic models. Polygenic risk scores (PRSs) were calculated to evaluate cumulative genetic effects. Results: No SNVs reached Bonferroni-corrected significance under any model. PRSs showed weak predictive ability for bleeding with apixaban. For rivaroxaban, regression indicated that ln C _{ss min} /D + 1 index increased with PRS, age, and 6-β-hydroxycortisol/cortisol ratio, but decreased with higher 6-β-hydroxycortisol and coronary heart disease presence. No statistically significant differences were found for the PharmGKB Level 3 variants rs1045642 (rivaroxaban) and rs2231142 (apixaban). Trends toward statistical significance were observed for the rs2472304-G variant in rivaroxaban users, rs6977165-C in apixaban users, and for the CYP3A4*1/*36 diplotype. Conclusion: Residual equilibrium concentration of DOACs, including dose-adjusted, did not independently predict bleeding risk in non-valvular AF patients. Variants rs2472304 and rs6977165 may warrant further investigation as potential contributors to bleeding risk.

Whole exome sequencing (WES) is essential for identifying genetic variants linked to diseases. This study compares available to date four exome enrichment kits: Agilent SureSelect Human All Exon v8, Roche KAPA HyperExome Probes, Vazyme VAHTS Target Capture Core Exome Panel, and Nanodigmbio NEXome Plus Panel v1. We evaluated target design, coverage statistics, and variant calling accuracy across these four different exome capture products. All kits showed high coverage completeness, with mean x10 coverage exceeding 97.5% and x20 coverage above 95%. Roche exhibited the most uniform coverage, indicated by the lowest fold-80 scores, while Nanodigmbio had more on-target reads due to fewer off-target reads. Variant calling performance, evaluated using in-lab standard E701 DNA sample, showed high recall rates for all kits, especially Agilent v8. All kits achieved an F-measure above 95.87%. Nanodigmbio had the highest precision with the fewest false positives but a slightly lower F-measure than other kits. This study also highlights the performance of new Chinese solutions from Vazyme and Nanodigmbio, which were comparable to Agilent v8 and Roche KAPA kits. These findings assist researchers and clinicians in selecting appropriate exome capture solutions.

IgA nephropathy (IgAN) is an autoimmune disorder which is believed to be non-monogenic. We performed an exome-wide association study of 70 children with IgAN and 637 healthy donors. The HLA allele frequencies were compared between the patients and healthy donors from the bone marrow registry of the Pirogov University. We tested 78,020 gene markers for association and performed functional enrichment analysis and transcription factor binding preference detection. We identified 333 genetic variants, employing three inheritance models. The most significant association with the disorder was observed for rs143409664 (PRAG1) in the case of the additive and dominant models (P_BONF = 1.808 × 10⁻¹⁵ and P_BONF = 1.654 × 10⁻¹⁵, respectively), and for rs13028230 (UBR3) in the case of the recessive model (P_BONF = 1.545 × 10⁻⁹). Enrichment analysis indicated the strongly overrepresented “immune system” and “kidney development” terms. The HLA-DQA1*01:01:01G allele (p = 0.0076; OR, 2.021 [95% CI, 1.322–3.048]) was significantly the most frequent among IgAN patients. Here, we characterized, for the first time, the genetic background of Russian IgAN patients, identifying the risk alleles typical of the population. The most important signals were detected in previously undescribed loci.

Background: Auditory Neuropathy Spectrum Disorder (ANSD) is often missed by common hearing screening tests, still accounting for up to 10% of hearing impairments. ANSD has an underlying genetic factor being mostly caused by pathogenic variants in 13 genes. Methods: We examined 122 children with impaired hearing, including 102 pediatric patients (mean age was 3.7±4.1 years) with sensorineural hearing loss (SNHL) of varying severity and 20 children with a clinically confirmed ANSD (mean age was 5.65±4.63 years). For children with SNHL, we genotyped the most frequent variants (c.35delG, c.167delT, c.235delC, c.313-326del14 and c.358-360delGAG) in the GJB2 gene using quantitative PCR. For children with a clinically confirmed ANSD, we performed the whole exome sequencing and studied the obtained variants in a custom panel of 248 genes. Results: Our findings show that fifty-six (54.9%) SNHL patients carried homozygous variants in GJB2 gene. In 12 (60%) ANSD patients, we detected variants in nucleotide sequences of the OTOF (25%), CDH23, TMC1, COL11A1, PRPS1 and HOMER2 genes (8 of which had not been previously described). Transient Evoked Otoacoustic Emissions testing revealed differences at 500 Hz (AS, p = 0.04181) and 4000 Hz (AD, p = 0.00126) between the ANSD and SNHL patient groups. The Auditory Steady-State Response (ASSR) test demonstrated significant differences at all frequencies (p < 0.01). When comparing the results obtained from the pure-tone audiometry and ASSR tests in ANSD patients revealed statistically significant differences at 500 (AD, AS) and 1000 (AD) Hz. Conclusions: These findings indicate that audiologists and otorhinolaryngologists should use the ASSR test in clinical practice for differential diagnosis of auditory neuropathies. According to the survey data from the parents of hearing-impaired children, rehabilitation was more successful in SNHL patients compared to ANSD patients.

Background/Objectives: Direct oral anticoagulants (DOACs) are first-line medications for stroke prevention in non-valvular atrial fibrillation (AF). However, variability in drug response poses risks of hemorrhagic or thromboembolic events. The role of genetics in determining DOAC safety is gaining attention, but evidence linking specific genetic polymorphisms to bleeding risk is lacking. Therefore, the aim of our study was to conduct an Exome-Wide Association Study with 198 non-valvular AF patients treated with rivaroxaban or apixaban, including 97 with bleeding complications and 99 without. Methods: DOAC plasma concentrations, 6-β-hydroxycortisol and cortisol levels in urine were measured for CYP3A4 phenotyping. Sequencing was performed on the DNBSEQ G-400 platform. Single nucleotide variants (SNV) associations with bleeding risk were assessed using logistic regression with additive, dominant, and recessive genetic models. Results: No SNVs reached Bonferroni-corrected significance in any genetic model. Polygenic risk scores (PRS) showed weak predictive ability for bleeding with apixaban. For rivaroxaban, regression indicated that ln Css min/D + 1 index increased with PRS, age, and 6-β-hydroxycortisol/cortisol ratio, but decreased with higher 6-β-hydroxycortisol and coronary heart disease presence. Conclusions: The findings revealed that the residual equilibrium concentration of anticoagulants, including dose-adjusted, cannot alone predict bleeding risk in non-valvular AF patients. No new genetic variants associated with bleeding risk were identified.