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

Area of Science:

• Genetics and Genomics
• Hematology
• Pediatric Medicine

Background:

• Inherited bone marrow failure syndromes (IBMFS) are rare genetic disorders affecting approximately 30% of pediatric bone marrow failure cases.
• These syndromes are often linked to developmental issues and an increased risk of developing cancers.
• Accurate molecular diagnosis is crucial for appropriate management and genetic counseling.

Purpose of the Study:

• To validate the laboratory performance and clinical utility of a custom-designed next-generation sequencing (NGS) panel for diagnosing IBMFS in pediatric patients.
• To assess the diagnostic yield of the CHOP IBMFS panel in a cohort of children with suspected IBMFS.
• To evaluate the panel's ability to detect various genetic variants, including single-nucleotide variants, small insertions/deletions, and copy number variations.

Main Methods:

• Laboratory validation of the CHOP IBMFS next-generation sequencing panel.
• Application of the panel to a cohort of 269 pediatric patients with suspected IBMFS.
• Analysis included identification of single-nucleotide variants, small insertions/deletions, and copy number variations in both mosaic and non-mosaic states.

Main Results:

• The CHOP IBMFS panel demonstrated high analytic accuracy: 100% sensitivity, ≥99.99% specificity, and 100% reproducibility.
• Molecular diagnoses of IBMFS were achieved in 21 cases (7.8%), with 61 pathogenic/likely pathogenic variants and 24 hypomorphic variants identified.
• Secondary findings, including early hematologic malignancies and hereditary cancer-predisposition syndromes, were noted in 9 cases (3.3%).

Conclusions:

• The CHOP IBMFS next-generation sequencing panel is a highly sensitive and specific tool for diagnosing inherited bone marrow failure syndromes in children.
• This NGS panel significantly increases the diagnostic yield for IBMFS compared to previous methods.
• The study supports the integration of NGS-based panel testing into routine diagnostics for pediatric patients with suspected IBMFS.