Acute myeloid leukemia (AML) is a complex hematological malignancy with multiple disease sub-groups defined by somatic mutations and heterogeneous outcomes. Although genome-wide association studies (GWAS) have identified a small number of common genetic variants influencing AML risk, the heritable component of this disease outside of familial susceptibility remains largely undefined. Here we perform a meta-analysis of four published GWAS plus two new GWAS, totalling 4710 AML cases and 12938 controls. We identify a new genome-wide significant risk locus for pan-AML at 2p23.3 (rs4665765; P=1.35x10-8; EFR3B, POMC, DNMT3A, DNAJC27) which also significantly associates with patient survival (P=6.09x10-3). Our analysis also identifies three new genome-wide significant risk loci for disease sub-groups, including AML with deletions of chromosome 5 and/or 7 at 1q23.3 (rs12078864; P=7.0x10-10; DUSP23) and cytogenetically complex AML at 2q33.3 (rs12988876; P=3.28x10-8; PARD3B) and 2p21 (rs79918355; P=1.60x10-9; EPCAM). We also investigated loci previously associated with risk of clonal hematopoiesis (CH) or clonal hematopoiesis of indeterminate potential (CHIP) and identified several variants associated with risk of AML. Our results further inform on AML etiology and demonstrate the existence of disease sub-group specific risk loci.

Myelofibrosis (MF) is a hematologic malignancy with a highly heterogeneous clinical course. Copy-neutral loss of heterozygosity (CN-LOH) may contribute to disease progression by promoting mutation homozygosity. Although single-nucleotide polymorphism (SNP) arrays are the gold standard for CN-LOH detection, optical genome mapping (OGM) has emerged as a promising alternative. In this multicenter study, the capability of OGM to detect CN-LOH in 78 patients with MF was assessed. OGM data were analyzed using both de novo (DN) and guided assembly pipelines (GA), followed by re-analysis of CN-LOH-positive cases with the Variant Intelligence Applications (VIA) software. Results were validated with SNP arrays. Compared with 45% for GA and 37% for DN, VIA demonstrated the highest concordance, confirming 90% (46/51) of CN-LOH events found by SNP arrays. Although VIA maintained a high concordance (90%) for all event sizes, GA (70%) and DN (61%) showed improved concordance for larger events (≥25 Mb). VIA also identified six CN-LOH events in 9p involving the JAK2 gene that were missed by DN and GA. Among 19 CN-LOH events detected by all three pipelines, 89% were confirmed by SNP arrays. Events ≥25 Mb exhibited greater concordance across platforms. These findings demonstrate that OGM, particularly when analyzed with VIA, is a sensitive and reliable method for CN-LOH detection in MF. However, in the absence of broader validation, confirmation with orthogonal methods remains necessary.

Exposure to chemotherapy and/or radiotherapy increases the risk of therapy-related myeloid neoplasms (t-MN), a heterogeneous group of disorders currently classified by treatment history rather than molecular features. Although germline predisposition has been suggested in approximately 20% of cases, its prevalence and clinical impact remain insufficiently defined. To address this, we analyzed 100 patients with t-MN by integrating clinical characteristics, prior treatment regimens, and genomic profiling. Somatic and germline variants were identified using targeted next-generation sequencing (NGS; n = 33) or whole-exome sequencing (n = 67). Somatic abnormalities, including cytogenetic and/or molecular alterations, were detected in 89.8% of patients. Germline variants were identified in 32.3% of cases, including mutations in cancer predisposition genes (19.8%) and myeloid disease-related genes (14.6%). Patient stratification by germline landscape and gene category defined two prognostic scenarios and three subgroups with distinct clinical outcomes. Patients harboring germline cancer predisposition variants exhibited were enriched for TP53 mutations, complex karyotypes, and had an adverse prognosis. In contrast, patients with germline myeloid-related variants and those without detectable germline variants showed recurrent mutations in TET2, DNMT3A, SF3B1, SRSF2, RUNX1 and ASXL1, were associated with normal karyotypes, and favorable outcomes. These findings underscore the importance of the germline landscape in t-MN pathogenesis and support its incorporation into disease classification and risk stratification. Notably, chemotherapy exposure was associated with complex karyotypes and poor prognosis in patients with germline cancer predisposition variants, highlighting a subgroup that may benefit from targeted surveillance and preventive strategies.

While the majority of myeloid neoplasms are sporadic, the increasing application of germline genetic testing has led the World Health Organization to designate 'Myeloid malignancies with germline predisposition' as a distinct clinical entity, carrying major implications for clinical care and research. Germline variants in the Sterile alpha motif domain-containing 9-like (SAMD9L) gene are specifically associated with an increased risk for these malignancies. In this study, we functionally modelled two novel SAMD9L variants-p.N697Y and p.K1294*-alongside two previously reported variants (p.T233N and p.H880Q). We generated heterozygous knock-in cellular models in the Human leukemia (HL-60 myeloid cell line) for each variant using homology-directed repair-based Clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9) gene editing. Functional assays, focused on proliferation and protein translation, confirmed that the p.T233N, p.N697Y and p.K1294* variants all caused a decreased rate of protein translation. These results provide functional evidence to fine-tune the classification of these SAMD9L variants and significantly advance our understanding of the molecular mechanisms by which SAMD9L variants drive inherited myeloid neoplasms.

Cytogenetic and molecular studies are the standard of care in the diagnosis of myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML), which are characterized by a highly heterogeneous genetic landscape. This complexity challenges accurate characterization, risk stratification, and treatment decision-making. Optical Genome Mapping (OGM) is emerging as a high-resolution technique capable of detecting cryptic structural variants (SVs) and copy number changes (CNVs). In this study, we analyzed 150 MDS and AML patients using standard diagnostic methods and complemented by OGM to assess its utility in resolving complex karyotypes and uncovering hidden genomic aberrations. The results revealed novel alterations and refined previous cytogenetic results (e.g., breakpoints, translocation partners) in 80% of cases, involving clinically relevant genes such as MECOM, KMT2A, and NUP98. Importantly, in complex karyotypes, undefined marker chromosomes and chromoanagenesis events were resolved by OGM, uncovering genomic aberrations with potential clinical relevance. Overall, our findings demonstrate that OGM enables a more comprehensive genomic characterization of patients, uncovering cryptic genomic alterations and resolving complex karyotypes in AML and MDS. The identified abnormalities have shown significant and potential clinical implications. Additionally, the discovery of novel alterations could offer insights into previously unknown pathogenic mechanisms, enhancing our understanding of AML and MDS pathogenesis.

Acute Myeloid Leukemia (AML) is a genetically and clonally heterogeneous blood malignancy characterized by somatic gene mutations influencing disease biology. Despite advances in genomic analyses, splicing alterations associated with AML mutations remain underexplored. In this study, we systematically analyzed 914 single nucleotide variants previously found in 1540 AML patients and integrated DNA and RNA sequencing data from an additional 639 cases obtained from the BeatAML and TCGA-LAML cohorts. We identified 125 somatic variants in 32 genes with predicted splicing impact, including traditionally categorized missense/nonsense mutations. Among the 36 variants tested experimentally, 17 were validated through RNA-seq and/or minigene assays, with the latter providing support when RNA-seq evidence was limited. Validated splicing-associated variants (SAVs) frequently induced exon skipping or cryptic splice site activation in AML-associated genes such as EZH2, FLT3, ASXL1, IDH1, and U2AF1. In several cases, these splicing changes altered conserved protein domains or were predicted to trigger nonsense-mediated decay. Our findings reveal a previously underappreciated contribution of cis-acting SAVs to AML pathogenesis, highlighting the need for integrative prediction–validation strategies to uncover their functional and potential therapeutic relevance.

Recent studies have demonstrated the association between constitutional ring chromosome 21 (r(21)c) and the development of B-cell acute lymphoblastic leukemia (B-ALL) with intrachromosomal amplification of chromosome 21 (iAMP21). iAMP21 acts as a driver which is often accompanied by secondary alterations that influence disease progression. Here, we report an atypical case of iAMP21 B-ALL with a unique molecular profile in the context of r(21)c. The onset of B-ALL occurred significantly earlier than previously reported in iAMP21-ALL, likely due to the presence of r(21)c. Only scarce cases of iAMP21 with concomitant PAX5 fusions have been reported. Through an extensive genomic characterization, the novel WWOX::PAX5 as well as 13q12.2 deletion involving FLT3 overexpression was found. These findings suggest that r(21)c may induce chromosomal instability on chromosome 21, triggering chromothripsis and leading to iAMP21-ALL. This case provides valuable insights to unravel the complex interplay between germline and somatic genetic alterations in leukemia. Moreover, it underscores the need for thorough genetic evaluation and multidisciplinary management in patients with syndromic presentation, particularly when rare genetic events may contribute to hematologic malignancies.

We analyzed the outcomes of 217 acute myeloid leukemia patients in complete remission who underwent allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning and post-transplant cyclophosphamide-based graftversus- host disease prophylaxis, aiming to assess the prognostic significance of genetic risk categories. In the overall cohort, the 2-year overall survival (OS) and event-free survival (EFS) were 77% (95% confidence interval [CI]: 71-83) and 72% (95% CI: 66-78), respectively. European LeukemiaNet (ELN)2022 risk stratification lacked prognostic value in HCT. Instead, we identified four risk categories with distinct impact on OS: standard risk (ELN2022 favorable/intermediate and adverse risk without high-risk genetic risk under the defined subcategories), intermediate risk (≥2 myelodysplasia-related gene mutations) (hazard ratio [HR]=2.23; 95% confidence interval [CI]: 1.14-4.92), adverse risk (complex karyotype, monosomal karyotype, inv(3)/t(3;3), KMT2A rearrangement) (HR=4.24; 95% CI: 2.00-9.02), and very adverse risk (TP53 mutations) (HR=6.81; 95% CI: 3.00-15.5). These categories demonstrated similar predictive power for EFS and cumulative incidence of relapse. Moreover, integrating pre-transplant measurable residual disease (MRD) refined risk stratification, identified MRD-negative patients with ≥2 myelodysplasia-related gene mutations whose OS and EFS were comparable to standard-risk patients. This refined classification improves the prognostic value of ELN2022 for acute myeloid leukemia patients undergoing allogeneic HCT with modern platform by integrating genetic features and MRD status to better guide post-transplant management.

Introduction After an allogeneic hematopoietic stem cell transplantation (allo-HSCT), a wide range of complications may occur. One of the less common, yet clinically significant, is the development of a donor-cell derived hematologic neoplasm (DCHN). Although their etiopathogenesis remains unclear, DCHNs are thought to arise from the combined effect of a genetic variant (either clonal hematopoiesis (CHIP) or germline variants) and the bone marrow microenvironment. The aim of this study was to assemble the largest national cohort of DCHNs to date, in order to characterize the disease, estimate the incidence and identify both somatic-CHIP and germline-predisposition variants. Methods We performed a multicenter retrospective study of patients diagnosed with DCHN. Donor origin of the neoplasm was suspected and confirmed by complete molecular donor chimerism (100%) and/or cytogenetic studies in cases of donor-recipient sex mismatch. A survey was distributed to Spanish centers performing allo-HSCTs in adults to collect essential clinical and genetic data related to the primary neoplasm (PN), peritransplant events and DCHN. When available, DNA from the donor (for related donors) and the DCHN was requested to perform: targeted-NGS panel enriched with frequently mutated genes in either myeloid or lymphoid neoplasms, depending on the DCHN lineage (x1400; CHIP characterization); and whole exome sequencing (WES) with a virtual panel of 455 predisposing genes (x100; germline predisposition). Results A total of 34 cases of DCHNs were identified across 23 Spanish transplant centers, diagnosed between 2007 and 2024. Notably, 63% of the cases (n=20) were diagnosed in the last 5 years, suggesting an increased awareness and detection of this complication. Regarding the transplant date, 68% of the allo-HSCTs were performed between 2013 and 2022 (n=21). Based on available National Transplant Organization (ONT) data, we estimated the incidence of DCHNs between 2020 and 2022 to be 0.29% of all transplants (n=8/2789), with a higher incidence in transplants from related (0.34%, n=6/1752) compared to unrelated donors (0.19%, n=2/1037). This aligns with the findings from our full cohort, where 31 of the 34 cases involved a related donor. The mean age at diagnosis of the PN was 48 years [range 18–73]. DCHNs diagnoses belonged to the myeloid (n=30) and the lymphoid lineage (n=3): acute myeloid leukemia (n=12), myelodysplastic syndrome (n=17), chronic myelomonocytic leukemia (n=1), mixed phenotype acute leukemia (n=1), cutaneous marginal zone B-cell lymphoma (n=1), cutaneous T-cell lymphoma (n=1) and lymphocytic lymphoma (n=1). Similarly, the PN that led to allo-HSCT were predominantly myeloid (n=24), while 9 were of lymphoid origin, including 4 acute lymphoblastic leukemias. Notably, in 9 cases, the DCHN appeared from a different hematopoietic lineage than the original neoplasia. Preparation for the transplant included in the 72% (n=23) of cases a reduced-intensity conditioning. Stem cell source was peripheral blood in 24 cases, bone marrow in 3, and cord blood in 2. At the time of donation, the mean age of the donors was 45 years [range 23-72]. The median latency between allo-HSCT and DCHN diagnosis was 50 months [range 16–390]. At data cutoff, 18 patients were deceased and 15 alive. The only remarkable cytogenetic characteristic was that chromosome 7 alterations were identified in 33.3% (n=10/30) of DCHNs. Genomic data was available for 28 DCHNs (23 paired with donor sample, 5 unpaired). Germline pathogenic variants in hematologic predisposition genes were detected in 11 donors and corresponding DCHN: DDX41 (n=6), CEBPA (n=2), biallelic CHEK2 (n=1), FH (n=1) and KMT2D (n=1). In two cases, donor material harbored CHIP-associated variants: one with a somatic SETBP1 mutation and the other with a monosomy 7 clone, both matching the clonal marker on the DCHN. Conclusions: Our findings confirm a strong predominance of DCHNs in related donor transplants. There is an increased awareness of the existence of DCHN and its implications, which can be deduced from the increase in diagnosed cases in the last five years. Germline predisposition was the main identifiable cause, present in 84.6% of genetically characterized cases. DDX41 and CEBPA accounted for 72.7% of these. Our findings support the implementation of routine germline screening in related donors, particularly targeting predisposition genes, to prevent donor-derived neoplasms.

Myelodysplastic syndromes/neoplasms (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. While genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3,233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations (CNAs), and copy-neutral loss of heterozygosity (cnLOH) were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91, 43, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and LOH at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not-otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow blast percentage across groups ranged from 1.5 to 10%, and the median overall survival from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of bone marrow blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and may inform future classification schemas and translational therapeutic research.

Genome-wide prenatal cell-free DNA (cfDNA) screening can be used to screen for a wide range of fetal chromosomal anomalies in pregnant patients. In this study, we describe our clinical experience with a genome-wide cfDNA assay in screening for common trisomies, sex chromosomal aneuploidies (SCAs), rare autosomal aneuploidies (RAAs), and copy-number variations (CNVs) in about 6000 patients over a three-year period at our hospital’s Prenatal Diagnostic Unit in Spain. Overall, 204 (3.3%) patients had a high-risk call, which included 76 trisomy 21, 21 trisomy 18, 7 trisomy 13, 29 SCAs, 31 RAAs, 31 CNVs, and 9 cases with multiple anomalies. The diagnostic outcomes were obtained for the high-risk cases when available, allowing for the calculation of positive predictive values (PPVs). Calculated PPVs were 95.9% for trisomy 21, 77.8% for trisomy 18, 66.7% for trisomy 13, 10.7% for RAAs, and 10.7% for CNVs. Pregnancy and birth outcomes were also collected for the majority of RAA and CNV cases. Adverse perinatal outcomes for some of these cases included preeclampsia, fetal growth restriction, preterm birth, reduced birth weight, and major congenital structural abnormalities. In conclusion, our study showed strong performance for genome-wide cfDNA screening in a large cohort of pregnancy patients in Spain.

INTRODUCTION: Related donors (RDs) for hematopoietic stem cell transplantation (HSCT) are increasingly older and comorbid. Meanwhile, germline predisposition has emerged as a new relevant issue in bone marrow failure conditions and myeloid neoplasms. The impact of those factors on donor and recipient safety constitutes a field of intensive clinical research. OBJECTIVE: The aim of this study is to describe our experience in evaluating RDs and to explore the potential apparition of donor-derived conditions in HSCT recipients from RDs. METHODS: We retrospectively analyzed the family history, hematological abnormalities, and autoimmune diseases of RDs evaluated for HSCT between January 2014 and December 2023, as well as the long-term outcomes of both donors and recipients. RESULTS: A total of 515 RDs were included, of whom 309 were HLA-identical donors (60%) and 206 were haploidentical donors (40%). Median donor age at the time of HSCT was 41 years (range 3-74), 70 (14%) RDs were 60 years or older, and 263 (51%) RDs were male. Myeloid malignancies were the most frequent HSCT indication (n=299, 58%). The median follow-up for the recipients was 45 months (range, 7-124). Seventy-eight RDs (15%) had oncological first-degree family history (FDFH) at evaluation. Additionally, 23 RDs (5%) had hematological FDFH at evaluation. Specifically, 8 (2%) were donors to a family member with myeloid neoplasia and had at least one other myeloid FDFH. Eighty-four (16%) RDs presented a hematological abnormality at initial evaluation or during follow-up: anemia (n=23, 4%), erythrocytosis (n=16, 3%), thrombocytopenia (n=6, 1%), thrombocytosis (n=6, 1%), macrocytosis (n=6, 1%), neutrophilia (n=5, 1%), eosinophilia (n=5, 1%), beta-thalassemia minor (n=4, 0.8%), monocytosis (n=3, 0.6%), monoclonal gammopathy of undetermined significance (n=3, 0.6%), and neutropenia (n=1, 0.2%). Nineteen (5%) had a mild autoimmune disease (mainly hypothyroidism or psoriasis). No recipient developed the oncological condition of their FDFH. One donor with a hematological FDFH at evaluation, carrying a pathogenic variant in DDX41, transmitted this alteration to the recipient, who developed donor cell leukemia. Another donor with mild monocytosis (0.8x109/L) at donation was later diagnosed with chronic myelomonocytic leukemia, which also developed in the recipient with identical molecular alterations. Donors with beta-thalassemia minor transmitted this condition to their recipients. A donor with hematological FDFH and macrocytosis at evaluation developed a newly onset, moderate thrombocytopenia after G-CSF administration. This patient was mobilizing poorly as compared with healthy donors and required two days of apheresis. No germline alteration was demonstrated in this family and the recipient has exhibited normal hematopoiesis. Another donor with similar alterations (macrocytosis and mild thrombocytopenia) mobilized poorly as well. In this case, hematopoiesis was also normal in the recipient, and the donor was eventually diagnosed with systemic sclerosis during follow-up. The analysis identified 7 patients carrying a cancer predisposition syndrome. In 3 donors, the pathogenic variant (in BRCA1, CHEK2, and ATM) was also proven and transmitted with the donation. In the other 4 cases, the donor was not studied. The CHEK2+ carrier relapsed after 5 months. The other recipients have not developed related abnormalities to date with a median follow-up of 50 months (range, 20-75). Finally, clonal hematopoiesis of indeterminate potential (CHIP) was transmitted from a 62-year-old healthy donor to a recipient. The recipient presented an extramedullary relapsed 6 years later without medullar involvement (where the CHIP was detected). The donor is currently under follow-up after developing a clonal cytopenia (anemia) of undetermined significance. CONCLUSION: Older donors and newly recognized germline predisposition neoplasms are significant challenges in the assessment of RDs today. Donors with more than one first-degree relative with myeloid disease should be evaluated cautiously within a multidisciplinary context. As recipient survival increases, genetic predisposition may become a more apparent clinical concern. It remains to be defined which donors and which genes should initially be studied, how to approach these findings, and the ethical dilemmas that this entails.

Introduction Donor-cell derived hematologic neoplasms (DCHN) are estimated to account for up to 2% of relapses following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, reported series are scarce and with limited cases, and no systematic registers have been established, hindering the complete understanding of this poor prognosis event. Additionally, it is still unknown the real weight of two phenomena put forward as main potential causes: germline predisposition (GP) and clonal hematopoiesis of indeterminate potential (CHIP). The aim of this study was to estimate the incidence of DCHN in centers performing allo-HSCT in Spain and to depict their clinical and biological data. Methods We contacted transplant and molecular biology units from 37 centers conducting allo-HSCT in adults in the last ten years in Spain. Collected variables included clinical and laboratory characterization of the primary neoplasm (PN) and the DCHN, as well as descriptive data of the main peri-transplant events. If available, sequencing data from the primary neoplasm, the DCHN, and the donor was collected. Results We registered 18 patients diagnosed of a DCHN from 15 of the 37 centers contacted, becoming the largest series of assembled cases to date. Fourteen cases (77.8%) were diagnosed in the last five years. Primary neoplasm diagnoses showed a predominance of myeloid lineage origin (77.8%) including 11 acute myeloid leukemia (AML) and 3 myelodysplastic syndrome (MDS) cases. In addition, 2 Hodgkin lymphoma (HL), and 1 mantle cell lymphoma (MCL) patients developed a DCHN. In one case, the allo-HSCT was performed due to aplastic anemia (AA). As for the type of DCHN, the majority of cases also developed a myeloid malignancy after the allo-HSCT (83%): seven developed an AML (six from AML, one from HL), and eight MDS (four from AML, three from MDS, one from AA). The three remaining cases were: one mixed-phenotype acute leukemia (from an AML case), one cutaneous marginal zone B-cell lymphoma (from the MCL case), and one cutaneous T-cell lymphoma (from HL). Notably, most cases had received reduced-intensity conditioning (70,6%). Regarding the type of donor, in 17 of the 18 cases, the donor was related, with a mean age of 36 years (range, 23-59). One donor met the criteria for poor mobilization of hematopoietic progenitors. The median latency period between the allo-HSCT and the DCHN diagnosis was 53 months (range, 16 months to 32 years). Nine patients (50%) died with the DCHN as the main cause. Of the 15 myeloid DCHN cases, 46,7% had abnormal cytogenetics, with 2 cases showing a del(20q). As to the genomic studies, we had molecular information from ten cases by NGS. Of those, we identified 6 cases with a potentially pathogenic germline variant responsible for the DCHN (DDX41, n=2; CEBPA, n=2; one with SAMD9L and one with a KIT variant). CHIP (acquired mutation VAF≥2% in myeloid driver gene) was not detected in the four cases where NGS sequencing was available in donor DNA before infusion. Finally, nine of the ten patients with DCHN NGS showed the acquisition of pathogenic somatic variants in recognized myeloid neoplasm-associated genes. Conclusions From our observational and retrospective results, we conclude: i) the majority of diagnoses are grouped in the last 5 years, which may reflect increased awareness of the phenomenon and/or the proportional increase of familial (haploidentical) allo-HSCTs; ii) the younger age of the donors and the marked majority of cases with related donors in our series suggest a predominance of a germline cause over CHIP transmission, and iii) although limited, the sequencing data also seem to support the presence of pathogenic germline variants in the donor as a relevant factor in the development of DCHN.

Patients aged 50 or above diagnosed with myeloid neoplasms (MNs) are typically not candidates for germline testing. However, approximately 8% carry pathogenic germline variants. Allogeneic haematopoietic stem cell transplantation (alloHSCT) remains an option for those aged over 50; neglecting germline testing could mask the risk for relative donor cell-derived MN. We propose a germline-augmented somatic panel (GASP), combining MN predisposition genes with a myeloid somatic panel for timely germline variant identification when initial testing is not indicated. Out of our 133 whole-exome-sequenced MN cases aged over 50 years, 9% had pathogenic/likely variants. GASP detected 92%, compared to 50% with somatic-only panel. Our study highlights the relevance of germline screening in MN, particularly for alloHSCT candidates without established germline-testing recommendations.