Targeted next generation sequencing panel based screening and diagnosis of bone marrow failure cohort reveals diverse genomic landscape of pathogenic germline variants

Abstract Introduction: Current study is a 4 year experience in diagnosis and screening of bone marrow failure cases using a targeted sequencing panel. Methods: A total of 171 cases underwent targeted NGS and were categorized as suspected inherited bone marrow failure syndrome (IBMFS) group (106/62%) and idiopathic aplastic anemia (IAA) group (65/38%) based on clinical and laboratory criteria. Results: 110 (64%) were pediatric (0-12 years) and 61 (36%) adolescent and adults (13-47 years). In suspected IBMFS group, 47 (44%) were positive for a pathogenic variation while in IAA group, 8 (12%) revealed a silent germline pathogenic variation. Whole exome sequencing performed in 15/61 suspected IBMFS group cases, revealed a clinically important variation in 3 (20%) cases. The targeted panel helped in establishing a diagnosis in 44% (27/61) of phenotypically heterogenous unclassified bone marrow failure syndrome cases and also led to amendment of clinical diagnosis in 5 (4.7%) of genotyped cases. Conclusion: Overall targeted NGS panel yield was comparable to western data, however, this was achievable at 1/5th the cost, making it a cost-effective panel for resource constraint settings.