Saturation genome editing of BAP1 functionally classifies somatic and germline variants

Area of Science:

• Genetics
• Genomics
• Molecular Biology

Background:

• Rare genetic variants pose challenges in disease association studies.
• BAP1 gene disruption is implicated in tumorigenesis and neurodevelopmental disorders.

Purpose of the Study:

• To experimentally characterize BAP1 variants using exhaustive saturation genome editing (SGE).
• To evaluate phenotypic associations of BAP1 variants in large human populations and disease collections.
• To identify potential pathological mechanisms and therapeutic targets for BAP1-associated diseases.

Main Methods:

• Performed SGE to experimentally characterize 18,108 unique BAP1 variants.
• Assessed variant function and evaluated phenotypic associations in UK Biobank and a tumor collection.
• Analyzed variants in cancer pedigrees and ClinVar, comparing cancer-associated to neurodevelopmental variants.

Main Results:

• Identified 6,196 BAP1 variants with abnormal functions.
• Disruptive germline BAP1 variants significantly correlated with elevated circulating IGF-1 levels.
• Developed a highly accurate variant classifier (>98% sensitivity and specificity) for precision interpretation.

Conclusions:

• BAP1 variants' functional impact and disease associations were experimentally determined.
• Elevated IGF-1 suggests a potential mechanism and therapeutic target for BAP1-related conditions.
• The developed classifier aids in precise interpretation of BAP1 variants for clinical applications.