Functional characterization of 105 factor H variants associated with aHUS: lessons for variant classification.

Area of Science:

• Genetics
• Complement System Biology
• Nephrology

Background:

• Atypical hemolytic uremic syndrome (aHUS) is a severe thrombotic microangiopathy.
• Complement dysregulation, often due to genetic variants, causes aHUS.
• Variants in the factor H (FH) gene (CFH) are common in aHUS and linked to poor outcomes.

Purpose of the Study:

• To functionally characterize aHUS-associated FH variants.
• To accurately classify CFH variants as pathogenic or benign.
• To improve clinical management of aHUS through precise variant interpretation.

Main Methods:

• Expression and in vitro functional characterization of 105 aHUS-associated FH variants.
• Validation of functional assays using 26 known FH variants.
• Assessment of variant rarity in control databases and prediction algorithm performance.

Main Results:

• Of 79 uncharacterized FH variants, 29 (36.7%) were identified as pathogenic based on altered expression or function.
• Rarity in control databases and prediction algorithms were found to be unreliable for FH variant classification.
• Functional data provided a basis for improved classification strategies.

Conclusions:

• Functional assays are essential for accurate FH variant classification in aHUS.
• Current prediction methods have limitations for FH variants.
• Individualized patient care for aHUS requires robust functional variant data.