Clinicopathologic Implications of Complement Genetic Variants in Kidney Transplantation

Area of Science:

• Nephrology
• Genetics
• Immunology

Background:

• Genetic variants in complement proteins are linked to thrombotic microangiopathy (TMA) and C3 glomerulopathy (C3G).
• Variants of uncertain significance (VUS) pose challenges for clinical risk assessment, especially post-kidney transplant.
• Functional characterization of VUS is needed to clarify their pathogenicity.

Purpose of the Study:

• To evaluate the clinicopathologic significance of genetic variants in TMA and C3G within a kidney transplant cohort.
• To functionally characterize variants of uncertain significance (VUS) in complement factor H (CFH).

Main Methods:

• Whole exome next-generation sequencing of complement genes in 76 kidney transplant patients (60 TMA, 16 C3G).
• Structural analysis and recombinant protein production for VUS.
• Functional characterization of VUS compared to wild-type (WT) CFH.
• Assessment of a family with combined CFH and membrane cofactor protein (MCP) variants.

Main Results:

• Ten CFH variants identified; four pathogenic, one likely benign, five VUS (I372V, I453L, G918E, T956M, L1207I).
• CFH variants I372V, I453L, and G918E were found to be deleterious.
• CFH variants T956M and L1207I showed normal functional activity.
• Common CFH polymorphisms and a family with combined MCP/CFH variants were also characterized.

Conclusions:

• Functional analysis is essential for determining the pathogenicity of CFH variants in TMA and C3G.
• Deleterious CFH variants impact disease etiology and recurrence risk in kidney transplant recipients.
• This study highlights limitations of predictive models and the importance of functional assays in complex clinical scenarios.