Background: The etiological diagnosis of chronic thrombocytopenia in children remains challenging and is often established by exclusion. In this article, we present the case of a patient in whom we used whole-exome sequencing (WES) to help identify the underlying cause and determine the appropriate treatment. Methods: Whole-exome sequencing was performed to clarify the genetic background of the disease. Based on the results, transmission electron microscopy (TEM) was also carried out to confirm or exclude the pathogenic role of the identified NBEAL2 gene variant and to assess the presence of gray platelet syndrome. Results: In this patient, despite the presence of the NBEAL2 gene variant, neither gray platelet syndrome nor a pathogenic role of the variant could be confirmed. However, the genetic findings identified by WES led to numerous additional investigations, causing a considerable burden on both the patient and the family. Conclusions: Our case highlights that WES testing, which is emerging in pediatric hematology practice, offers not only diagnostic advantages but also pitfalls. Whole-exome sequencing has recently emerged as a new diagnostic tool and has been available nationwide in pediatric hematology-oncology care in Hungary for just over two years. While personalized treatment strategies for benign hematologic diseases increasingly rely on high-throughput genetic testing, the clinical application of WES requires a cautious, critical evaluation of results. Despite the method’s promise, the heterogeneity of the findings underscores the need to interpret WES results carefully and to place them in a clinical context in every case.

Reliable detection of structural variants (SVs) and copy number variations (CNVs) is crucial in the contemporary diagnostics of pediatric B-cell acute lymphoblastic leukemia (B-ALL). However, limitations of commonly used conventional and molecular cytogenetic methods may hinder the accurate genetic characterization of patients. Optical genome mapping (OGM) offers a reliable alternative by enabling high-resolution, genome-wide detection of CNVs and SVs. Chromosomal aberrations were screened using OGM in 51 children with B-ALL. The results were compared with those of karyotyping, fluorescence in situ hybridization (FISH), digital multiplex ligation-dependent probe amplification (digitalMLPA), and targeted RNA sequencing (RNA-seq). OGM data showed high congruency with karyotyping and FISH findings, detecting clinically relevant variants beyond G-banding results and unraveling a complex KMT2A fusion undetected by FISH. Gene fusions involved in complex ETV6::RUNX1 translocations, but not detected by RNA-seq, were confirmed using FISH. Normalization of OGM copy number values with DNA-index-improved concordance with FISH-derived copy numbers in near-tri/tetraploid cases. In the peripheral regions of OGM variants (fringe-zones), a novel evaluation strategy called 'FriZone' was applied, which significantly improved the concordance between OGM and digitalMLPA. In addition, a co-segregation analysis revealed strong associations between ETV6::RUNX1 fusion and deletions of ETV6, RAG2, and NR3C2. OGM uncovered complex rearrangements undetected by widely used methods in 15% of cases, improving genetic classification and risk stratification in 10% of the patients. The FriZone analysis and normalization by DNA-index provide a refined, more accurate approach to OGM variant interpretation, facilitating the efficient application of OGM in clinical diagnostics. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The vast majority of childhood cytopenias are transient, mostly secondary, and not the consequence of primary bone marrow processes. Yet, every few months we see patients in the pediatric hematology centers of the Hungarian Pediatric Oncology Network in whom repeated bone marrow sampling and extensive laboratory hematological investigations do not lead to a diagnosis and the cytopenia persists chronically. In these cases, the identification or exclusion of genetically determined benign or premalignant hematological conditions – such as congenital neutropenia, hereditary hemolytic or dyserythropoietic anemia, inherited thrombocytopenia, congenital bone marrow failure syndrome – is essential for modern therapy planning. In correctly selected pediatric patients with chronic cytopenia, modern high-throughput molecular genetic testing by next-generation sequencing is the most cost-effective diagnostic option, and its early use avoids many invasive interventions and inappropriate therapeutic attempts. At the initiative of Semmelweis University, a national molecular genetic diagnostics program was launched to map the etiology, epidemiology and prognosis of hereditary chronic cytopenias in children in Hungary. In the present work, we summarize the technical details of the testing modality and the indications we propose to apply in clinical practice. As a proof of concept, we present a discovery cohort of 30 patients selected according to these indications: 67% of them were identified with a gene variation that at least partially explained the phenotype, 47% with a variation that revised the diagnosis initially assumed by the treating physician, and 43% with a variation that determined the next substantive therapeutic decision. Of these, 45% were likely pathogenic or pathogenic aberrations and 55% were variants of unknown clinical significance. We propose to consider and apply this high-throughput molecular genetic modality, which generates significant clinical benefit and has a high diagnostic success rate according to our own and international data presented, as a priority element of the hematological diagnostic workflow in our country, within a regulated, professional framework. Orv Hetil. 2025; 166(1): 3–19.

In paediatric B-cell acute lymphoblastic leukaemia (B-ALL), bone marrow (BM) minimal residual disease (MRD) monitoring is well standardised but requires invasive sampling, while cerebrospinal fluid (CSF) assessments for central nervous system (CNS) infiltration remain unreliable. This study investigates extracellular long noncoding RNAs (lncRNAs) as potential biomarkers for B-ALL. BM, peripheral blood (PB), and CSF samples from B-ALL patients under 18 years were fractionated to isolate cell-free components. An 89-target lncRNA screening panel was developed through a literature review. RNA isolation methods were optimised, and screening was conducted on cell-free BM samples from 11 patients at days 0 (diagnosis) and 33 (remission) of induction therapy. Using droplet digital PCR (ddPCR), we analysed five selected lncRNAs in body cell-free CSF. Five lncRNAs—LINC01013 (p = 0.007), AC002464.1 (p = 0.013), AC002454.1 (p = 0.035), BX293535.1 (p = 0.006), and LINC00958 (p = 0.036)—were significantly overexpressed in day 0 cell-free BM samples compared to day 33 remission samples. These lncRNAs were detectable by ddPCR in BM and PB samples but not in CSF. Extracellular lncRNAs show promise as less invasive MRD biomarkers in BM and PB. However, low CSF concentrations limit their use for monitoring CNS infiltration.

Risk-adapted treatment protocols conferred remarkable improvement in the survival rates of pediatric acute lymphoblastic leukemia/lymphoma (ALL/LBL). Nevertheless, clinical management is still challenging in certain molecular subgroups and in the presence of alterations associated with an increased rate of relapse. In this study, disease-relevant genomic and transcriptomic profiles were established in a prospective, multicenter, real-world cohort involving 192 children diagnosed with ALL/LBL. Gene fusions were detected in 34.9% of B-ALL and 46.4% of T-ALL patients, with novel chimeric genes involving JAK2, KMT2A, PAX5, RUNX1, and NOTCH1, and with KMT2A-rearranged patients displaying the worst 3-year event-free survival (P 1/4 .019). Nonsynonymous mutations were uncovered in 74.9% of the analyzed patients, and pairwise scrutiny of genetic lesions revealed recurrent clonal selection mechanisms commonly converging on the same pathway (eg, Ras, JAK/ STAT, and Notch) in individual patients. Investigation of matched diagnostic and relapse samples unraveled complex subclonal variegation, and mutations affecting the NT5C2, TP53, CDKN2A, and PIK3R1 genes, emerging at the time of relapse. TP53 and CREBBP mutations, even as subclonal aberrations, were associated with shorter 3-year event-free survival among all patients with B-ALL (TP53 mutant vs wild-type: P = .008, CREBBP mutant vs wild-type: P = .010), and notably, B-ALL patients showing no measurable residual disease on day 33 could be further stratified based on TP53 mutational status (P < .001). Our in-depth molecular characterization performed across all risk groups identified novel opportunities for molecularly targeted therapy in 55.9% of high-risk and 31.6% of standard/intermediate-risk patients. (c) 2025 THE AUTHORS. Published by Elsevier Inc. on behalf of the United States & Canadian Academy of Pathology. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).

A gyermekkori cytopeniák döntő többsége átmeneti, leginkább szekunder jelenség, és nem primer csontvelői folyamatok következménye. Mégis néhány havonta találkozunk olyan betegekkel a Magyar Gyermekonkológiai Hálózat kötelékébe tartozó gyermekhematológiai centrumokban, akiknél többszöri csontvelői mintavétel és széles körű laboratóriumi hematológiai kivizsgálás sem vezet diagnózishoz, a cytopenia pedig krónikusan fennáll. A korszerű terápiatervezéshez ezekben az esetekben elengedhetetlen a genetikailag determinált benignus vagy praemalignus hematológiai kórállapotok – mint például congenitalis neutropeniák, hereditaer haemolyticus vagy dyserythropoeticus anaemiák, örökletes thrombocytopeniák, örökletes csontvelő-elégtelenségi szindrómák – megállapítása vagy kizárása. A helyesen szelektált krónikus cytopeniás gyermekpopulációban a modern, újgenerációs szekvenálásra épülő, nagy áteresztőképességű molekuláris genetikai vizsgálat a leginkább költséghatékony diagnosztikus megoldás, amelynek korai alkalmazásával számos invazív beavatkozás és nem megfelelő terápiás próbálkozás elkerülhető. A Semmelweis Egyetem kezdeményezésére nemzeti szinten szervezett molekuláris géndiagnosztikai programot indítottunk a gyermekkori örökletes krónikus cytopeniák hazai etiológiai, epidemiológiai és prognosztikai feltérképezésére. Jelen közleményünkben a vizsgálati modalitás technikai részleteit és a klinikai gyakorlatban javaslatunk szerint alkalmazandó indikációs köreit összegezzük. Koncepciónk igazolásaként bemutatunk az indikációs körök szerint kiválasztott, 30 betegből álló mintapopulációt: közöttük 67%-ban a fenotípust legalább részben magyarázó, 47%-ban az eredetileg a kezelőorvos által feltételezett diagnózist revideáló, 43%-ban pedig a következő érdemi terápiás döntést meghatározó géneltérést azonosítottunk. Ezek 45%-a volt valószínűleg patogén vagy patogén aberráció, 55%-a pedig ismeretlen klinikai szignifikanciájú variáns. A jelentős klinikai hasznot generáló, közleményünkben bemutatott saját és nemzetközi adatok szerint is nagy találati aránnyal jellemezhető nagy áteresztőképességű molekuláris genetikai modalitást szabályozott szakmai keretek között a gyermekhematológiai kivizsgálás hazánkban is elérhető, kiemelt elemeként javasoljuk számba venni és alkalmazni a jövőben. Orv Hetil. 2025; 166(1): 3–19.

OBJECTIVES:CD49f is an adhesion molecule present on malignant lymphoblasts in B-cell acute lymphoblastic leukemia; it is associated with a poor prognosis. CD49f expression has been proposed as a marker for measurable residual disease (MRD) marker, but this marker has yet to be implemented in clinical practice. METHODS:In this study, we used flow cytometry to detect CD49f expression by leukemic blasts in paired bone marrow and cerebrospinal fluid samples at diagnosis and bone marrow at day 15 of treatment. RESULTS:At diagnosis, 93% of bone marrow and 100% of cerebrospinal fluid lymphoblasts expressed CD49f. The intensity of CD49f expression statistically significantly increased during treatment (P < .001). In MRD-negative end-of-treatment samples, only a small population of hematogones expressed CD49f. Interestingly, the intensity of CD49f expression varied among the different groups of recurrent genetic abnormalities. The ETV6::RUNX1 fusion and ETV6::RUNX1 combined with the high hyperdiploid group were associated with increased expression, whereas the Philadelphia-like group showed low CD49f expression. The lower CD49f expression at diagnosis predicted a lower MRD rate at day 15 of treatment. CONCLUSIONS:We concluded that CD49f can be used as an MRD marker and possible prognostic factor in B-cell acute lymphoblastic leukemia.

Despite remarkable improvements in the survival of pediatric acute lymphoblastic leukemia (ALL), sensitive detection and clinical management of central nervous system leukemia (CNSL) are still immensely challenging. Blast cells residing in the CNS but not circulating in the cerebrospinal fluid (CSF) remain undetected by current diagnostic methods, preventing a truly risk-adapted anti-leukemic treatment in this compartment. We examined the clinical applicability of the molecular marker microRNA (miR)-181a quantified in the cell-free CSF to evaluate the level of CNS involvement and to optimize patient stratification based on CNS status. Normalized copy number of miR-181a was longitudinally profiled using droplet digital PCR, and the results were compared with the degree of leukemic involvement of the CNS. After combining cytospin- and flow cytometry (FCM) data with miR-181a expression, we could stratify previously ambiguous cases and reclassify patients into a CNS-positive/miR-significant group (mean +/- SE for miR-181a copies: 3300.70 +/- 809.69) bearing remarkable infiltration as well as into CNS-minimal/miR-significant and CNS-minimal/miR-minimal groups differentiating putative, clinically significant occult CNSL cases (2503.50 +/- 275.89 and 744.02 +/- 86.81 copies, respectively, p = 1.13 x 10-6). In summary, miR-181a expression is a promising biomarker for CNSL detection, facilitating the robust identification of patients who could benefit from intensified CNS-directed therapy.

RASopathies are congenital diseases that manifest in childhood with symptoms and potential complications, typically associated with an elevated tumour predisposition risk. The heterogeneous symptoms involve mostly central nervous, cardiovascular, musculoskeletal systems and skin, and modified growth pattern. From molecular perspective, the function of a key protein involved in Ras signalling is impaired, leading to disrupted regulation of cell growth and division. It is crucial to uncover genetic history, analyse tumour and cardiac involvement pattern along four generation pedigree and depict minor anomaly pattern. Upon clinical suspicion a stepwise approach to molecular testing is recommended to confirm or rule out the specific RASopathy. Post-test genetic counselling should address potential complications, developmental and follow-up strategies in line with current guidelines. Cascade pedigree segregation analysis according to the inheritance pattern should be offered to family planning parents and potentially affected family members. In case of certain specific organ involvement or complications, targeted therapeutics are available, highlighting the importance of early diagnosis.

Background Recurrent genetic lesions provide basis for risk assessment in pediatric acute lymphoblastic leukemia (ALL). However, current prognostic classifiers rely on a limited number of predefined sets of alterations. Methods Disease-relevant copy number aberrations (CNAs) were screened genome-wide in 260 children with B-cell precursor ALL. Results were integrated with cytogenetic data to improve risk assessment. Results CNAs were detected in 93.8% ( n = 244) of the patients. First, cytogenetic profiles were combined with IKZF1 status ( IKZF1 normal , IKZF1 del and IKZF1 plus ) and three prognostic subgroups were distinguished with significantly different 5-year event-free survival (EFS) rates, IKAROS-low ( n = 215): 86.3%, IKAROS-medium ( n = 27): 57.4% and IKAROS-high ( n = 18): 37.5%. Second, contribution of genetic aberrations to the clinical outcome was assessed and an aberration-specific score was assigned to each prognostically relevant alteration. By aggregating the scores of aberrations emerging in individual patients, personalized cumulative values were calculated and used for defining four prognostic subgroups with distinct clinical outcomes. Two favorable subgroups included 60% of patients ( n = 157) with a 5-year EFS of 96.3% (excellent risk, n = 105) and 87.2% (good risk, n = 52), respectively; while 40% of patients ( n = 103) showed high ( n = 74) or ultra-poor ( n = 29) risk profile (5-year EFS: 67.4% and 39.0%, respectively). Conclusions PersonALL, our conceptually novel prognostic classifier considers all combinations of co-segregating genetic alterations, providing a highly personalized patient stratification.

Background: Asparaginase is a key component of chemotherapy protocols for the treatment of lymphoblastic malignancies among children. Adequate asparagine depletion is an important factor to achieve optimal therapeutic outcomes. Methods: Over a 3.5 year period, 106 patients were monitored for asparaginase activity (329 samples) in a single center of the Hungarian Pediatric Oncology–Hematology Group. In Hungary, three asparaginase products are available: native E. coli ASNase (Kidrolase), a pegylated form of this enzyme (Pegaspargase) and another native product from Erwinia chrysanthemi (Erwinase). A retrospective data analysis was performed. Results: In 81% (268/329) of our patients, AEA levels were in the optimal therapeutic range of over 100 IU/L. Of 106 patients, 13 (12%) were diagnosed with ‘silent inactivation’. Conclusions: Monitoring of AEA can help to identify patients with ‘silent inactivation’ and their asparaginase therapy can thus be optimized.

Background: Minimal residual disease (MRD) is one of the most valuable independent prognostic factors in acute lymphoblastic leukemia (ALL). Bone marrow (BM) aspiration, however, is an invasive process. Previous studies have shown that microRNAs (miR) and extracellular vesicle (EV)-related miRs show different expression profiles at the presence of malignant cells compared to healthy controls. In our previous project, we have reported that two miRs previously described to be overexpressed in blasts were significantly decreased over the first week of the therapy of patients with ALL in the platelet free plasma fraction (PFP) of peripheral blood samples (PB). The aim of the current study was to assess the relation between day 15 flow cytometry (FC) MRD and expression of miR-128-3p and miR-222-3p miRs in exosome-enriched fraction (EEF) of PFP to evaluate whether their expression in EEF correlates with day 15 FC MRD more precisely. Methods: PB was collected from 13 patients diagnosed with pediatric pre-B ALL at 4 time points. Expression of miR-128-3p and miR-222-3p was measured by qPCR in PFP and EEF. Results: Positive correlation was found between changes of miR-128-3p expression in EEF or PFP by day 8 of chemotherapy and day 15 FC MRD (rEEF = 0.99, pEEF = 1.13E-9 and rPFP = 0.99, pPFP = 4.75E-9, respectively). Furthermore, the decrease of miR-128-3p in EEF by day 15 of treatment also showed a positive correlation with day 15 FC MRD (rEEF = 0.96; pEEF = 4.89E-5). Conclusion: Our results show that circulating miRs are potential biomarkers of ALL MRD, asmiR-128-3p level both in PFP and EEF predicts day 15 FC MRD. In addition, the assessment of the EEF gave a more promising result.

Pediatric acute myeloid leukemia (AML) represents a major cause of childhood leukemic mortality, with only a limited number of studies investigating the molecular landscape of the disease. Here, we present an integrative analysis of cytogenetic and molecular profiles of 75 patients with pediatric AML from a multicentric, real-world patient cohort treated according to AML Berlin-Frankfurt-Münster protocols. Targeted next-generation sequencing of 54 genes revealed 17 genes that were recurrently mutated in >5% of patients. Considerable differences were observed in the mutational profiles compared with previous studies, as BCORL1, CUX1, KDM6A, PHF6, and STAG2 mutations were detected at a higher frequency than previously reported, whereas KIT, NRAS, and KRAS were less frequently mutated. Our study identified novel recurrent mutations at diagnosis in the BCORL1 gene in 9% of the patients. Tumor suppressor gene (PHF6, TP53, and WT1) mutations were found to be associated with induction failure and shorter event-free survival, suggesting important roles of these alterations in resistance to therapy and disease progression. Comparison of the mutational landscape at diagnosis and relapse revealed an enrichment of mutations in tumor suppressor genes (16.2% versus 44.4%) and transcription factors (35.1% versus 55.6%) at relapse. Our findings shed further light on the heterogeneity of pediatric AML and identify previously unappreciated alterations that may lead to improved molecular characterization and risk stratification of pediatric AML.

Topic: 1. Acute lymphoblastic leukemia - Biology & Translational Research Background: Advances in therapeutic strategies of pediatric acute lymphoblastic leukemia (ALL) improved 5-year survival rates; however, the clinical management of disease progression and relapse remains challenging. Profiling molecular markers with prognostic and/or predictive significance in individual patients is crucial for refined risk assessment and precise patient stratification, underlining the importance of comprehensive molecular characterization. Aims: To interrogate the genomic and transcriptomic landscape of Hungarian children diagnosed with ALL in order to identify alterations with prognostic and therapeutic relevance, and to facilitate a more advanced, risk-adapted therapy selection for clinical decision-making. Methods: Diagnostic bone marrow samples with a mean blast percentage of 78.4% were investigated from 180 patients diagnosed with B-ALL (n=150) or T-ALL (n=30). Additionally, samples drawn at the time of relapse were analyzed from 19 patients. Gene fusions were identified with the TruSight RNA Pan-Cancer Panel targeting 1,385 genes, while mutation screening was performed using a custom QIASeq Targeted DNA Panel covering 102 disease-relevant genes. Copy number alterations were screened with multiplex ligation-dependent probe amplification using SALSA P335, P202 and P383 probemixes. Measurable residual disease (MRD) monitoring was performed by flow cytometry. Results: Gene fusions were identified in 34.9% of B-ALL and 46.4% of T-ALL patients, with ETV6-RUNX1, STIL-TAL1, P2RY8-CRLF2 and TCF3-PBX1 being the most common alterations. Five novel fusions involving JAK2, PAX5, KMT2A and RUNX1 genes were also observed. Targeted mutation screening revealed a higher number of aberrations in T-ALL patients (B-ALL: 2.01±1.88 vs. T-ALL: 3.86±3.00; p<0.001). In B-ALL, variants most frequently affected RAS-pathway genes (KRAS 18.4%, NRAS 17.8% and FLT3 10.2%), while NOTCH1 (58.6%), PHF6 (27.5%), PTEN (17.2%) and WT1 (17.2%) were the most commonly altered genes in T-ALL. IKZF1 deletion was observed in 18.1% of B-ALL patients, with eight of them showing IKZF1plus genotype. The vast majority (75.0%) of UBA2 mutations accompanied ETV6-RUNX1 fusion. Besides all patients with BCR-ABL1 fusion harboring IKZF1 deletion, BCR-ABL1-like subtype showed significant association with IKZF1 deletions (p=0.028). NT5C2 mutations, undetectable at diagnosis were identified at relapse in three patients. All CCND3-mutant cases (n=9) were MRD-negative with flow cytometry at day 33 and only one patient had detectable blasts at day 78. NOTCH1 and WT1 mutation frequently co-occurred with MRD-positivity at days 33 and 78. Scrutiny of the dynamics of early therapy response from diagnosis to day 15 revealed a slower decrease of MRD in the presence of RUNX1 mutation with high variant allele frequency (‘high burden’, VAF≥25%; wild type vs. ‘high burden’ p=0.004). The dynamics of MRD decline from day 15 to day 78 differed in TP53-mutant patients: a slower response to therapy was observed in high burden cases (‘high burden’ vs. wild type, ‘high burden’ vs. ‘low burden’; p<0.001). Survival analysis showed significantly shorter 3-year overall and event-free survival in RUNX1 and/or TP53 ‘high burden’ patients (OS: 92.3% vs. 50.0%, p=0.0001; EFS: 87.0% vs. 50.0%, p=0.002). Summary/Conclusion: With novel gene fusions and uncovered associations between the dynamics of MRD decline, TP53 and RUNX1 high burden mutations in this real-world cohort, our dataset provides valuable, clinically relevant insights to the genomic and transcriptomic landscape of children diagnosed with ALL. Keywords: Pediatric, ALL, Prognosis, Mutation analysis

Central nervous system (CNS) involvement is a leading cause of therapy-refractory pediatric acute lymphoblastic leukemia (pALL), which is aggravated by underdiagnosing CNS disease with the currently used cell-based approach of cerebrospinal fluid (CSF) diagnostics. Our study focused on developing novel subcellular CNS leukemia indicators in the CSF and the bone marrow (BM) of patients with pALL. Serial liquid biopsy samples (n = 65) were analyzed by Elisas to measure the level of essential proteins associated with blast cell CNS trafficking, vascular endothelial growth factor A (VEGF-A) and integrin alpha 6 (ITGA6). In CSF samples from early induction chemotherapy, VEGF-A concentration were uniformly elevated in the CNS-positive group compared to those patients without unambiguous meningeal infiltration (9 vs Nine patients, Δc = 17.2 pg/ml, p = 0.016). Expression of miR-181a, a VEGFA-regulating microRNA which showed increased level in CNS leukemia in our previous experiments, was then paralleled with VEGF-A concentration. A slight correlation between the levels of miR-181a and VEGF-A indicators in CSF and BM samples was revealed (n = 46, Pearson’s r = 0.36, p = 0.015). After validating in international cohorts, the joint quantification of miR-181a and VEGF-A might provide a novel tool to precisely diagnose CNS involvement and adjust CNS-directed therapy in pALL.

Despite improving cure rates in childhood acute lymphoblastic leukemia (ALL), therapeutic side effects and relapse are ongoing challenges. These can also affect the central nervous system (CNS). Our aim was to identify germline gene polymorphisms that influence the risk of CNS events. Sixty single nucleotide polymorphisms (SNPs) in 20 genes were genotyped in a Hungarian non-matched ALL cohort of 36 cases with chemotherapy related acute toxic encephalopathy (ATE) and 544 controls. Five significant SNPs were further analyzed in an extended Austrian-Czech-NOPHO cohort (n = 107 cases, n = 211 controls) but none of the associations could be validated. Overall populations including all nations’ matched cohorts for ATE (n = 426) with seizure subgroup (n = 133) and posterior reversible encephalopathy syndrome (PRES, n = 251) were analyzed, as well. We found that patients with ABCB1 rs1045642, rs1128503 or rs2032582 TT genotypes were more prone to have seizures but those with rs1045642 TT developed PRES less frequently. The same SNPs were also examined in relation to ALL relapse on a case-control matched cohort of 320 patients from all groups. Those with rs1128503 CC or rs2032582 GG genotypes showed higher incidence of CNS relapse. Our results suggest that blood-brain-barrier drug transporter gene-polymorphisms might have an inverse association with seizures and CNS relapse.