Uncovering the Genetic Etiology of Inherited Bone Marrow Failure Syndromes Using a Custom-Designed Next-Generation Sequencing Panel

Abstract

Inherited bone marrow failure syndromes (IBMFS) are a group of heterogeneous disorders that account for approximately 30% of pediatric bone marrow failure cases and are often associated with developmental abnormalities and cancer predisposition. We report the laboratory validation and clinical utility of a large custom-designed NGS panel, CHOP IBMFS panel, for the diagnosis of IBMFS in a large cohort of pediatric patients. This panel demonstrated excellent analytic accuracy with 100% sensitivity, ≥99.99% specificity, and 100% reproducibility on validation samples. Two hundred sixty-nine patients suspected to have IBMFS were investigated using this NGS panel to identify single nucleotide variants (SNVs), small insertions/deletions (indels) and copy number variations (CNVs) in mosaic or non-mosaic status. Sixty-one pathogenic/likely pathogenic (P/LP) variants (54 SNVs/indels and 7 CNVs), and 24 hypomorphic variants were identified, resulting in the molecular diagnosis of IBMFS in 21 cases (7.8%) and exclusion of IBMFS with a diagnosis of another blood disorder in 10 cases (3.7%). Secondary findings including evidence of early hematologic malignancies and other hereditary cancer-predisposition syndromes were observed in 9 cases (3.3%). CHOP IBMFS panel displays high sensitivity and specificity and has resulted in a significant increase in the diagnostic yield of IBMFS. This study demonstrates that NGS-based panel testing should be part of the routine diagnostic workup for suspected IBMFS patients.