Clinicopathologic Implications of Complement Genetic Variants in Kidney Transplantation

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 prima...

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Autores principales:	Zhen Ren, Stephen J. Perkins, Latisha Love-Gregory, John P. Atkinson, Anuja Java
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	kidney transplantation complement complement regulators atypical hemolytic uremic syndrome variants of uncertain significance thrombotic microangiopathy Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/a669c7cafeef4f408eaaed65d1542cc7
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spelling	oai:doaj.org-article:a669c7cafeef4f408eaaed65d1542cc72021-12-01T13:18:10ZClinicopathologic Implications of Complement Genetic Variants in Kidney Transplantation2296-858X10.3389/fmed.2021.775280https://doaj.org/article/a669c7cafeef4f408eaaed65d1542cc72021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fmed.2021.775280/fullhttps://doaj.org/toc/2296-858XGenetic 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.Zhen RenStephen J. PerkinsLatisha Love-GregoryJohn P. AtkinsonAnuja JavaFrontiers Media S.A.articlekidney transplantationcomplementcomplement regulatorsatypical hemolytic uremic syndromevariants of uncertain significancethrombotic microangiopathyMedicine (General)R5-920ENFrontiers in Medicine, Vol 8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	kidney transplantation complement complement regulators atypical hemolytic uremic syndrome variants of uncertain significance thrombotic microangiopathy Medicine (General) R5-920
spellingShingle	kidney transplantation complement complement regulators atypical hemolytic uremic syndrome variants of uncertain significance thrombotic microangiopathy Medicine (General) R5-920 Zhen Ren Stephen J. Perkins Latisha Love-Gregory John P. Atkinson Anuja Java Clinicopathologic Implications of Complement Genetic Variants in Kidney Transplantation
description	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.
format	article
author	Zhen Ren Stephen J. Perkins Latisha Love-Gregory John P. Atkinson Anuja Java
author_facet	Zhen Ren Stephen J. Perkins Latisha Love-Gregory John P. Atkinson Anuja Java
author_sort	Zhen Ren
title	Clinicopathologic Implications of Complement Genetic Variants in Kidney Transplantation
title_short	Clinicopathologic Implications of Complement Genetic Variants in Kidney Transplantation
title_full	Clinicopathologic Implications of Complement Genetic Variants in Kidney Transplantation
title_fullStr	Clinicopathologic Implications of Complement Genetic Variants in Kidney Transplantation
title_full_unstemmed	Clinicopathologic Implications of Complement Genetic Variants in Kidney Transplantation
title_sort	clinicopathologic implications of complement genetic variants in kidney transplantation
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/a669c7cafeef4f408eaaed65d1542cc7
work_keys_str_mv	AT zhenren clinicopathologicimplicationsofcomplementgeneticvariantsinkidneytransplantation AT stephenjperkins clinicopathologicimplicationsofcomplementgeneticvariantsinkidneytransplantation AT latishalovegregory clinicopathologicimplicationsofcomplementgeneticvariantsinkidneytransplantation AT johnpatkinson clinicopathologicimplicationsofcomplementgeneticvariantsinkidneytransplantation AT anujajava clinicopathologicimplicationsofcomplementgeneticvariantsinkidneytransplantation
_version_	1718405132258902016

Clinicopathologic Implications of Complement Genetic Variants in Kidney Transplantation

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