Genetic variant profile in a cohort of inherited bone marrow failure patients from North india

Inherited bone marrow failure syndromes (IBMFS) represent a genetically heterogeneous group of. disorders often overlapping with acquired aplastic anemia and myelodysplastic neoplasms. Accurate genetic diagnosis is essential for guiding management, stem cell transplantation, and cancer surveillance. Data on IBMFS genetics from India remain limited. This study aimed to characterize the genetic variant profile in a North Indian cohort of patients presenting with bone marrow failure (BMF). We retrospectively analyzed 167 patients with clinical suspicion of BMF evaluated at a single tertiary center over four years. Clinical features, somatic abnormalities, hematological parameters, and bone marrow findings were systematically documented. Chromosomal breakage studies and PNH flow cytometry were performed where indicated. Genetic testing included targeted NGS panels (98 cases) and whole exome sequencing (69 cases), with variants interpreted using ACMG guidelines. The median patient age was 10 years (range 1 month-44 years), with a male-to-female ratio of 2.4:1. Physical anomalies were present in 29.3% of patients. Pancytopenia was the most frequent hematological finding (69%). NGS identified 113 distinct variants in 94/167 patients (56.3%) Pathogenic or likely pathogenic variants were found in 28.7% of cases. FANCA was the most frequently mutated gene, followed by RPS19, SBDS, TERT, and ADA2. Variants associated with Fanconi anemia were predominant (22 cases), followed by dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome. Emerging syndromes involving DNAJC21, ERCC6L2, and MYSM1 were also identified. Genetic testing revealed diverse IBMFS-associated variants, with FANCA mutations being most common. Incorporating comprehensive NGS into diagnostic workflows is critical for differentiating IBMFS from acquired BMF, guiding therapy, donor selection, and long-term surveillance.