We report incidence and deep molecular characteristics of lineage switch in 182 pediatric patients affected by B-cell precursor acute lymphoblastic leukemia (BCP-ALL), who were treated with blinatumomab. We documented six cases of lineage switch that occurred after or during blinatumomab exposure. Therefore, lineage conversion was found in 17.4% of all resistance cases (4/27) and 3.2% of relapses (2/63). Half of patients switched completely from BCP-ALL to CD19-negative acute myeloid leukemia, others retained CD19-positive B-blasts and acquired an additional CD19-negative blast population: myeloid or unclassifiable. Five patients had KMT2A gene rearrangements; one had TCF3::ZNF384 translocation. The presented cases showed consistency of gene rearrangements and fusion transcripts across initially diagnosed leukemia and lineage switch. In two of six patients, the clonal architecture assessed by IG/TR gene rearrangements was stable, while in others, loss of clones or gain of new clones was noted. KMT2A-r patients demonstrated very few additional mutations, while in the TCF3::ZNF384 case, lineage switch was accompanied by a large set of additional mutations. The immunophenotype of an existing leukemia sometimes changes via different mechanisms and with different additional molecular changes. Careful investigation of all BM compartments together with all molecular –minimal residual disease studies can lead to reliable identification of lineage switch.

Damaging mutations of the Angiotensin I-converting enzyme (ACE) that result in low ACE levels may increase the risk of developing late-onset Alzheimer’s disease (AD). We quantified blood ACE levels in EDTA-plasma from 147 subjects with 23 different heterozygous ACE mutations (and 70 controls) and estimated the effect of these mutations on ACE phenotype, using a set of monoclonal antibodies (mAbs) to ACE and two ACE substrates. We identified several mutations in both ACE domains (including the most frequent ACE mutation, Y215C), which led to decreased ACE levels in the blood, and thus could be considered as putative risk factors for late-onset AD. The precipitation of several ACE mutants (Q259R, A725P, C734Y) by specific mAbs changed significantly, and therefore, these mAbs could be markers of these mutations. Analysis of 50 of the most frequent ACE mutations demonstrates that more than 1.5% of the adult population may have mutations which lead to decreased ACE levels, and thus, the role of low ACE levels in the development of AD may be underappreciated. Intriguingly, statistical and cluster analyses of longevity patients revealed trends towards higher frequency of cognitive impairment among affected individuals with damaging ACE mutations. Systematic analysis of blood ACE levels in patients with various ACE mutations identifies individuals with low blood ACE levels who may be at increased risk for late-onset AD. Patients with transport-deficient ACE mutations theoretically could benefit from therapeutic treatment with a combination of chemical and pharmacological chaperones and proteasome inhibitors, as was demonstrated previously on a cell model of the transport-deficient ACE mutation Q1069R. Moreover, clinical association analysis suggests a trend linking damaging ACE mutations with increased risk of cognitive impairment.

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.

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.

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.

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.