Clinicopathologic Implications of Complement Genetic Variants in Kidney Transplantation

Frontiers in Medicine

Stephen J. Perkins¹  Zhen Ren²  Anuja Java³  John P. Atkinson⁴  Latisha Love-Gregory⁵ 

[1] Department of Structural and Molecular Biology, Division of Biosciences, University College London, London, United Kingdom;Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States;Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States;Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States;Genomic and Pathology Services, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States;

关键词: kidney transplantation;    complement;    complement regulators;    atypical hemolytic uremic syndrome;    variants of uncertain significance;    thrombotic microangiopathy;   

DOI  :  10.3389/fmed.2021.775280

来源: DOAJ

【 摘 要 】

Genetic testing has uncovered rare variants in complement proteins associated with thrombotic microangiopathy (TMA) and C3 glomerulopathy (C3G). Approximately 50% are classified as variants of uncertain significance (VUS). Clinical risk assessment of patients carrying a VUS remains challenging primarily due to a lack of functional information, especially in the context of multiple confounding factors in the setting of kidney transplantation. Our objective was to evaluate the clinicopathologic significance of genetic variants in TMA and C3G in a kidney transplant cohort. We used whole exome next-generation sequencing to analyze complement genes in 76 patients, comprising 60 patients with a TMA and 16 with C3G. Ten variants in complement factor H (CFH) were identified; of these, four were known to be pathogenic, one was likely benign and five were classified as a VUS (I372V, I453L, G918E, T956M, L1207I). Each VUS was subjected to a structural analysis and was recombinantly produced; if expressed, its function was then characterized relative to the wild-type (WT) protein. Our data indicate that I372V, I453L, and G918E were deleterious while T956M and L1207I demonstrated normal functional activity. Four common polymorphisms in CFH (E936D, N1050Y, I1059T, Q1143E) were also characterized. We also assessed a family with a pathogenic variant in membrane cofactor protein (MCP) in addition to CFH with a unique clinical presentation featuring valvular dysfunction. Our analyses helped to determine disease etiology and defined the recurrence risk after kidney transplant, thereby facilitating clinical decision making for our patients. This work further illustrates the limitations of the prediction models and highlights the importance of conducting functional analysis of genetic variants particularly in a complex clinicopathologic scenario such as kidney transplantation.

【 授权许可】

Unknown