Integrated proteogenomic analysis for inherited bone marrow failure syndrome

Area of Science:

• Proteomics
• Genomics
• Hematology
• Molecular Diagnostics

Background:

• Inherited bone marrow failure syndromes (IBMFS) are a group of rare genetic disorders.
• Accurate diagnosis and screening for IBMFS can be challenging, often requiring complex genetic testing.
• Advanced proteomic techniques offer potential for deeper biological insights and diagnostic development.

Purpose of the Study:

• To perform an integrated proteogenomic analysis of various IBMFS subtypes.
• To identify distinct proteomic signatures associated with different IBMFS conditions.
• To develop and evaluate a proteomic-based diagnostic assay for IBMFS screening.

Main Methods:

• Utilized in-depth data-independent acquisition proteomic analysis for comprehensive protein quantification.
• Integrated proteomic data with genomic information for a holistic view of IBMFS.
• Employed unsupervised clustering to identify proteomic subgroups.
• Developed and validated a targeted proteomic assay for large-scale screening.

Main Results:

• Identified eight distinct proteomic clusters (C1-C8) within the IBMFS cohort.
• Observed downregulation of the ribosomal pathway in Diamond-Blackfan anemia (DBA) and Shwachman-Diamond syndrome (SDS).
• Found significantly reduced SBDS protein in SDS patients, with some cases undiagnosed by DNA sequencing alone.
• Detected significantly reduced ADH5 protein in patients with ADH5/ALDH2 deficiency.
• Demonstrated the efficacy of a targeted proteomic assay for detecting reduced SBDS and ADH5 levels in screening.

Conclusions:

• Integrated proteogenomic analysis provides valuable biological insights into IBMFS.
• Proteomic profiling can identify specific molecular defects, aiding in diagnosis beyond genetic sequencing.
• A proteomic-based assay shows promise for rapid, large-scale screening and diagnosis of IBMFS, addressing a clinical need.