Q- hemegenome: The Qatar national registry for germline predisposition to myeloid and other hematologic malignancies Free

Background Recognition of germline predisposition to myeloid and other hematologic malignancies has increased substantially in recent decades, significantly influencing disease risk stratification, prognosis, therapeutic decision-making, donor selection for allogenic stem cell transplant , and family -screening. Given the high prevalence of consanguinity in Qatar and the MENA region, these populations are at a higher risk of developing such conditions, highlighting the urgent need for regional data and structured registries.

Methods and Results We retrospectively analyzed cases of myeloid malignancies, including acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative disorders, and bone marrow failure syndromes, in which germline predisposition was clinically suspected, from 01 Jan 2015 to 01 Jan 2025 at the National Center for Cancer Care and Research (NCCCR) in Doha, Qatar. This registry is supported by the Hematology Precision Tumor Board, where complex somatic and germline variants are reviewed by a multidisciplinary team.

Patients underwent whole-exome sequencing (WES) or targeted panel testing for probands and targeted variant testing for possible bone marrow donors and at-risk family members. Eligibility was based on the ELN 2016 and 2022 classification of myeloid neoplasms with germline predisposition and British Society of Hematology guidelines (2024). This initiative serves as the foundation for establishing Q-HemeGenome, Qatar's first national hematogenomic registry.

The aim of the registry is to capture and integrate clinical phenotype, laboratory results, and genomic data from adult patients diagnosed with hematologic malignancies and bone marrow failure syndromes in Qatar.

We have identified individuals carrying germline genetic variants in genes such as TP53, associated with Li-Fraumeni syndrome, GATA2 gene, and other variants in genes including FANCI, CXCR4, WAS, MPL, ERCC6L2, and ANKRD26 (A detailed table is available ). Notably, all three of our patients with Li-Fraumeni syndrome developed acute leukemia, each displaying a distinct spectrum of disease manifestations and clinical outcomes. Unfortunately, two patients passed away before they could undergo transplantation, while the third achieved remission and successfully received a bone marrow transplant.

Additionally, we identified a large local cohort of patients with Griscelli syndrome carrying a founder novel variant in the RAB27A gene associated with phenotypic heterogeneity in Qatari families. Griscelli syndrome is a unique condition prevalent in the region that predisposes patients to fatal hemophagocytic lymphohistiocytosis (HLH) and lymphoid malignancies. These findings play a crucial role in guiding therapeutic strategies, donor selection, and long-term risk management for both patients and their families.

Conclusion The Q-HemeGenome registry is the first national initiative that capture germline predisposition to hematological malignancies in Qatar. Through this registry, we identified highly consanguineous and complex families with multiple hematological diseases, facilitating accurate diagnosis and enabling personalized management.

It provides a platform for long-term follow-up, enables the discovery of novel variants with potential for prevention and drug development and personalized therapeutic strategies . Additionally, it establishes a regional resource for understanding the genetic landscape of hematological malignancies in the MENA region.