Expanding genetic landscape of inherited bone marrow failure syndromes: Insights from the Canadian Inherited Marrow Failure Registry ( <scp>CIMFR</scp> ) (2001–2023)

Inherited bone marrow failure syndromes (IBMFSs) are genetically heterogeneous with an expanding spectrum of causative genes. Recent molecular advances are thought to have contributed to genetic identification, yet the true gain in diagnostic yield remains unclear. Accordingly, this study aims to investigate the evolving genetic landscape of IBMFSs using data from the Canadian Inherited Marrow Failure Registry by analysing patients enrolled from the 2001-2010 cohort to the 2011-2023 cohort. Among 407 genetically tested patients, 308 (75.7%) underwent molecular diagnosis, with variants identified in 62 distinct genes. These genes encompass diverse cellular pathways, including DNA repair, telomere maintenance, transcription, RNA splicing, ribosome biogenesis, nuclear envelope, Golgi, endoplasmic reticulum and mitochondrial integrity, cell signalling, cytokine receptor activity and cytoskeletal regulation. A total of 453 variants were identified, including pathogenic copy number variants in 12.7% (39/308) of cases, representing 10.4% (47/453) of all variants. Diagnostic yield increased from 51.6% in 2001-2010 to 75.7% in 2001-2023, and genetic testing enabled classification of 17.5% (54/308) of previously unclassified cases. These findings underscore the rapid growth of IBMFS genetic knowledge and the crucial value of comprehensive testing, although 24.3% of cases remain unresolved, likely due to novel syndromes and unrecognised IBMFS-related genes.