Lucy C. Fox

Inherited bone marrow failure syndromes (IBMFS) are monogenic disorders characterized by single or multilineage cytopenias from hypoproliferative dyshematopoiesis. Diagnosis is challenging because of substantial clinical and pathological overlap between individual IBMFS entities and acquired diseases such as immune aplastic anemia. Conventional genetic testing using targeted panels or whole exome sequencing incompletely captures the spectrum of pathogenic variation, leaving a substantial proportion of cases undiagnosed. We evaluated the utility of upfront whole genome and transcriptome sequencing (WGTS) in 237 patients with suspected IBMFS using non-hematopoietic DNA. Median age was 29 years (range 3 months-76 years) and 34.6% were under 18 years. Clinically-accredited sequencing was performed with real-time return of results to guide patient management and familial testing. A molecular diagnosis was established in 87/237 patients (36.7%), spanning hereditary thrombocytopenia, telomere biology disorders, Diamond-Blackfan anemia, severe congenital neutropenia, Shwachman-Diamond syndrome, Fanconi anemia and other IBMFS. A further four patients were diagnosed with non-hematological genetic conditions and seven patients with secondary actionable findings. Novel pathogenic mechanisms including retrotransposon-mediated gene disruption were identified. Further, novel associations with primary IBMFS-like presentations (THRA) as well as definitive evidence of gene-disease associations (MEIS1, TUBB) were established. Acceptability of WGTS based on the established Theoretical Framework of Acceptability was high among patients and carers. Upfront WGTS in suspected IBMFS provides a high diagnostic yield when compared with other genomic approaches, identifies actionable genomic abnormalities, and expands the spectrum of disease mechanisms and gene associations in IBMFS.

Current cell and gene therapies lack clinically practical mechanisms to selectively promote or suppress therapeutic cells in vivo, a limitation that is particularly acute in patients requiring ongoing immunosuppression. This includes gene therapy for immune dysregulation syndromes, and antigen-specific or chimeric antigen receptor (CAR) T-cell therapy for patients requiring immunosuppression (eg, transplant recipients), in which both pathogenic and therapeutic cells may be suppressed. Here, we develop a multiplex prime-editing platform that converts commonly used immunosuppressive drugs into tools for in vivo control of T-cell therapies via defined, pathway-specific drug resistance. Focusing initially on gene therapy, prime editing efficiently edited loci of multiple pathogenic variants associated with immune dysregulation in primary human T-cells and corrected the HAVCR2 driver mutation in T cells from multiple patients with subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Comprehensive genomic, transcriptional, immunophenotypic, and clonal analyses demonstrated minimal off-target perturbation. Multiplexed gene correction and drug-resistance editing of T-cells from patients with SPTCL enabled selective in vivo expansion of corrected cells under immunosuppressive pressure in humanized mouse models and exhibited retained sensitivity to alternative agents permitting rapid in vivo suppression. Extending this approach, prime-edited, drug-resistant antigen-specific and CAR T cells retained effector function despite pharmacologic immunosuppression, demonstrating the generalizability of this platform to diverse cellular therapies. Together, these findings establish multiplex prime editing as a promising preclinical framework for generating drug-controllable T-cell therapies, enabling selective in vivo modulation in settings in which immunosuppression cannot be withdrawn.

In 1952, a US Army pediatrician named Ogden Bruton ran serum electrophoresis on an eight-year-old boy with recurrent pneumococcal sepsis and noted the complete absence of gamma-globulin [1]. This w...

Germline GATA2 deficiency is a pleiotropic condition 1-8 characterized by numerous phenotypes, including monocytopenia, immunodeficiency, microbial susceptibilities, and high rates of myeloid malignancies 1,8. Accurate curation of germline GATA2 variants is critical for patient care and requires well-defined phenotypes associated with GATA2 deficiency. The many phenotypes attributed to the condition render a simple description of GATA2 deficiency difficult, complicating the development of GATA2 variant curation rules. Therefore, the Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) sought to define GATA2 deficiency based on a statistical comparison of phenotype data. To do so, the MM-VCEP systematically analyzed phenotype data and applied statistical comparisons to define the phenotypic features of GATA2 deficiency to inform germline variant curation. The MM-VCEP assembled an international cohort of 339 people with clinically diagnosed GATA2 deficiency from 16 centers in seven countries. The 73 phenotypes of these individuals were compared statistically to those of control participants from the UK Biobank (UKBB). We compared single phenotypes as well as combinations of two, three, and four phenotypes in people with clinically diagnosed GATA2 deficiency to UKBB controls. We defined GATA2 deficiency as any of the 2,903 combinations of two or three phenotypes with log10Odds Ratio ≥3 (OR ≥ 1000). This definition of GATA2 deficiency will inform gene-specific phenotypic criteria used in GATA2 variant curation guidelines that will facilitate standardized variant curation by clinical laboratories worldwide.

Background: Immunosuppressive therapy (IST) is standard first‐line treatment for severe aplastic anaemia (AA) in patients ineligible for allogeneic transplantation. Thrombopoietin receptor agonists (TPO‐RAs) are increasingly added to IST to improve haematologic recovery, but long‐term safety remains uncertain. Methods: We conducted a PRISMA‐guided systematic review and meta‐analysis. MEDLINE, EMBASE and CENTRAL were searched from inception to April 2025. Randomised controlled trials and observational studies comparing TPO‐RA plus IST with IST alone were analysed separately using random‐effects models. The primary outcome was overall haematologic response at 6 months; secondary outcomes included response at 3 and 12 months, complete response, survival, relapse and clonal evolution. Results: Twenty studies (2 randomised and 18 observational) were included. In randomised trials, TPO‐RA plus IST showed a non‐significant trend towards higher overall response at 6 months (OR 2.01; 95% CI 0.76–5.28), while complete response was significantly higher at 3 and 6 months. Observational studies consistently demonstrated higher overall and complete response rates. No significant differences were observed in survival, relapse or clonal evolution. Conclusion: Limited randomised evidence does not demonstrate statistically significant benefit across all outcomes, while observational data suggest potential haematologic advantages. Further high‐quality trials are required to clarify the effectiveness and long‐term safety of adding a TPO‐RA to IST in AA. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission

Deleterious germline DDX41 variants are the leading cause of heritable predisposition to myelodysplastic neoplasia and acute myeloid leukemia (MDS/AML). Accurate classification of pathogenicity is crucial for managing patients and their families. The absence of specific guidelines, along with late-onset disease, incomplete penetrance, and founder variants, poses challenges in clinical and laboratory practice. We aggregated a synthetic cohort (ASC) of DDX41 germline and somatic variants from 35 studies, including 1796 cases among 53686 patients, plus an additional 832 cases from non-cohort publications. We aimed to leverage the DDX41 -ASC to develop and refine ACMG/AMP criteria on case enrichment (PS4 ), somatic associations ( PP4 ), and computational prediction ( PP3/BP4 ). Analysis confirmed that deleterious germline DDX41 variants are most common in MDS/AML. A quasi-case-control study with ancestry matching revealed overestimated odds ratios for variants in underrepresented groups. Exploiting germline–somatic associations, we developed a Bayesian multinomial model that updates the odds of pathogenicity based on the presence and number of somatic patterns. Comparison of prediction tools showed that AlphaMissense outperformed REVEL in sensitivity. These results were integrated into an online tool to facilitate the consistent application of criteria. Overall, this comprehensive analysis of DDX41 -ASC provides an evidence framework to inform the development of DDX41 -specific curation guidelines.

Deleterious germline DDX41 variants are the leading cause of heritable predisposition to myelodysplastic syndrome and acute myeloid leukemia (MDS/AML). Accurate classification of pathogenicity is crucial for managing patients and their families. The absence of specific guidelines, along with late-onset disease, incomplete penetrance, and founder variants, poses challenges in clinical and laboratory practice. We aggregated a synthetic cohort (ASC) of DDX41 germline and somatic variants from 36 studies, including 1802 cases among 53795 patients, plus an additional 832 cases from non-cohort publications. We aimed to leverage the DDX41 -ASC to develop and refine ACMG/AMP criteria on case enrichment (PS4 ), somatic associations ( PP4 ), and computational prediction ( PP3/BP4 ). Analysis confirmed that deleterious germline DDX41 variants are most common in MDS/AML. A quasi-case-control study with ancestry matching revealed overestimated odds ratios for variants in underrepresented groups. Exploiting germline–somatic associations, we developed a Bayesian multinomial model that updates the odds of pathogenicity based on the presence and number of somatic patterns. Comparison of prediction tools showed that AlphaMissense outperformed REVEL in sensitivity. These results were integrated into an online tool to facilitate the consistent application of criteria. Overall, this comprehensive analysis of DDX41 -ASC provides an evidence framework to inform the development of DDX41 -specific curation guidelines.

Background: The bone marrow failure syndromes (BMFS) are clinically heterogeneous conditions with both inherited and acquired etiologies. Optimal care is often challenged by the complexity of these disorders and gaps in healthcare delivery. The Evaluating Multidisciplinary Bone maRrow fAilure CarE (EMBRACE) study is a multi‐stage hybrid implementation‐effectiveness study designed to explore the nature of issues faced by patients with BMFS and their physicians, and to develop, implement, and evaluate a comprehensive model of care.Methods: To identify barriers to optimal BMFS care, we conducted semi‐structured interviews with patients and patient advocates, followed by a nationwide survey of physicians involved in BMFS management. Thematic analysis was performed on interview data, and survey responses were analysed to identify common challenges and areas for improvement.Results: Interview themes elicited included: (i) limited disease‐specific awareness and resources, (ii) challenges in attaining genetic care, (iii) the ongoing impact of complex care needs, (iv) the perceived value of genetic testing, and (v) the importance of specialised healthcare professionals.Physician surveys indicated a desire for affordable genomic testing, assistance with result interpretation and genetic counselling/cascade testing of extended kindred, a forum for complex case discussion and advice regarding management strategies.Responses from patients, advocates and physicians, along with existing best‐practice guidelines, were then used to develop a 10‐component model of care aimed at addressing identified issues.Conclusions: The EMBRACE study has established a stakeholder‐informed, multidisciplinary care framework for patients with BMFS. This care programme continues to undergo evaluation and audit consistent with principles of an implementation‐effectiveness study to determine both patient and physician satisfaction, and iterative refinement to provide optimum care.