Re-Analysis of Next Generation Sequencing Gene Panel Data By Normalized Coverage Values Reveals Previously Undetected Copy Number Variations in Inherited Bone Marrow Failure Syndromes

Background:Inherited bone marrow failure syndromes (IBMFSs) comprise a group of genetic disorders affecting blood cell production in bone marrow, resulting in single or multilineage cytopenias. Patients with IBMFSs often have physical malformations and are at risk of developing leukemia and solid tumors. With advances in sequencing technologies, causal nucleotide-level mutations can readily be identified in many IBMFSs. In about half of IBMFS cases, however, a molecular mutation is not detected. Copy number variation (CNVs) have been reported to cause IBMFSs. Unfortunately, genome-wide methods to identify CNVs have major limitations as they may miss small lesions (e.g. by oligonucleotide or CGH arrays) or may have low sensitivity due to low read depths (e.g. by whole genome sequencing).