Upfront whole genome and transcriptome sequencing to improve diagnosis in inherited bone marrow failure syndromes

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.