Heterozygous Pathogenic COL4A3 and COL4A4 Variants (Autosomal Dominant Alport Syndrome) Are Common, and Not Typically Associated With End-Stage Kidney Failure, Hearing Loss, or Ocular Abnormalities

Abstract

The term “autosomal dominant (AD) Alport syndrome” is often used to describe the condition associated with heterozygous pathogenic COL4A3 or COL4A4 variants and has largely replaced “thin basement membrane nephropathy (TBMN).” AD Alport syndrome implies that affected individuals develop end-stage kidney failure (ESKF) as well as the typical Alport hearing loss and ocular abnormalities, but these features have been considered rare with TBMN.Recent studies suggest that ESKF occurs in 14% to 30% of those with heterozygous pathogenic COL4A3 or COL4A4 variants but confirm that the hearing loss and ocular defects occur uncommonly if at all. Uncertainty over the risk of ESKF has persisted.However all the cited studies of heterozygous pathogenic COL4A3 or COL4A4 variants and kidney failure are and with ESKF have heterozygous pathogenic variants in COL4A3 and COL4A4 occur as often as that AD Alport syndrome ESKF as often as the heterozygous pathogenic COL4A3 and COL4A4 variants are often AD Alport syndrome is ESKF often and occurs in of those with pathogenic COL4A3 or COL4A4 variants the of individuals with heterozygous pathogenic COL4A3 or COL4A4 variants to are to develop kidney those at The term “autosomal dominant (AD) Alport syndrome” is often used to describe the condition associated with heterozygous pathogenic COL4A3 or COL4A4 variants and has largely replaced “thin basement membrane nephropathy (TBMN).” AD Alport syndrome implies that affected individuals develop end-stage kidney failure (ESKF) as well as the typical Alport hearing loss and ocular abnormalities, but these features have been considered rare with studies suggest that ESKF occurs in 14% to 30% of those with heterozygous pathogenic COL4A3 or COL4A4 variants but confirm that the hearing loss and ocular defects occur uncommonly if at all. Uncertainty over the risk of ESKF has all the cited studies of heterozygous pathogenic COL4A3 or COL4A4 variants and kidney failure are and with ESKF have heterozygous pathogenic variants in COL4A3 and COL4A4 occur as often as that AD Alport syndrome ESKF as often as the heterozygous pathogenic COL4A3 and COL4A4 variants are often AD Alport syndrome is ESKF often and occurs in of those with pathogenic COL4A3 or COL4A4 variants the of individuals with heterozygous pathogenic COL4A3 or COL4A4 variants to are to develop kidney those at Alport syndrome is kidney hearing and ocular of and of the The of the term AD Alport syndrome has been individuals with heterozygous pathogenic COL4A3 or COL4A4 of of of the Alport implies these individuals develop as well as the features of hearing loss and ocular have and risk of ESKF is AD Alport syndrome is The that all heterozygous COL4A3 or COL4A4 variants as AD Alport syndrome that condition occurs in of the of of of the Alport The to basement membrane and of have heterozygous pathogenic COL4A3 or COL4A4 variants in of of pathogenic COL4A3 variants in and Alport is the features of the of or kidney is AD Alport ESKF considered in studies of of membrane of of is associated with and basement membrane syndrome in features and of with and and of basement membrane The hearing loss membrane and the ocular as and in basement membrane and the of Alport syndrome and basement membrane features in Alport and and the pathogenic COL4A3 or COL4A4 have individuals with basement membrane basement membrane studies have to the of hearing loss and ocular defects with pathogenic heterozygous COL4A3 or COL4A4 of affected individuals in hearing loss in and ocular in of and features of basement membrane nephropathy COL4A3 or COL4A4 with individuals the typical hearing loss in and ocular features in and features of dominant Alport the hearing loss and ocular are with heterozygous pathogenic COL4A3 or COL4A4 in the of the hearing and of the ocular are typical of Alport syndrome and features have COL4A3 or COL4A4 and of these studies that of and of individuals with AD Alport syndrome of and features of basement membrane nephropathy COL4A3 or COL4A4 and features of dominant Alport are of 14% to of of COL4A3 and COL4A4 with kidney and features of dominant Alport in in of heterozygous in the associated with and to and kidney and failure in basement membrane has that AD and Alport syndrome are in the of pathogenic COL4A3 variants in and Alport and these studies have all been to have the to the risk of ESKF in of with AD Alport the of to variants is the in of kidney failure as in the studies have the of pathogenic and variants in with or kidney failure have studies have that heterozygous pathogenic COL4A3 and COL4A4 variants occur as often as pathogenic variants and kidney in Alport of in kidney to end-stage of and kidney in with kidney of kidney kidney of kidney in of pathogenic and variants in with kidney variants COL4A4 Alport syndrome and kidney in Alport considered of in kidney to end-stage with of and kidney or in with kidney and with of kidney in kidney kidney in or with or with of kidney in kidney end-stage kidney in with the of and variants in the the of pathogenic COL4A4 and variants in the of kidney of pathogenic COL4A3 variants in and Alport pathogenic variants to and and variants that affected in the The of in and and with the of in kidney of membrane of heterozygous pathogenic COL4A3 or COL4A4 variants in in of the and pathogenic variants in in of pathogenic COL4A3 variants in and Alport pathogenic COL4A3 and COL4A4 variants as often as pathogenic variants in the and if of these is AD Alport syndrome occurs as often as Alport pathogenic COL4A3 and COL4A4 variants as to ESKF as as often in with kidney occur as that heterozygous pathogenic variants in COL4A3 and COL4A4 are to ESKF in ESKF in Alport with pathogenic have variants that are associated with or kidney variants are Alport syndrome to the in the is in and kidney failure in have Alport syndrome as often as of but are to develop kidney syndrome in and the that used to the of COL4A3 and COL4A4 to variants and and in the of pathogenic COL4A3 variants in and Alport have of pathogenic COL4A3 variants in and Alport used all the and is that of with pathogenic variants develop kidney failure the of and that is at the of Alport in and in Alport and in and to Alport syndrome of the with pathogenic variants are and of with have kidney failure features and of with and The risk of with pathogenic ESKF of as of with pathogenic are with risk of kidney failure the of the to kidney failure risk is the risk with pathogenic is the risk of with pathogenic ESKF the of is the of these or risk of kidney failure pathogenic COL4A3 or COL4A4 variants is that or is the risk of ESKF the of pathogenic COL4A3 or COL4A4 variants is and the of are to these heterozygous pathogenic COL4A3 or COL4A4 variants in The with kidney failure cited individuals with Alport features to have and have in in the of with pathogenic variants and with heterozygous COL4A3 or COL4A4 or variants are often and have the ESKF Alport in and in Alport and in and to Alport syndrome suggest that pathogenic variants the are and associated with kidney failure of but these the of heterozygous pathogenic COL4A3 or COL4A4 variants the of of kidney and of all the heterozygous variants in the COL4A3 and COL4A4 are and have risk of risk kidney and kidney Alport in and in and with kidney kidney and the of and kidney with pathogenic heterozygous COL4A3 or COL4A4 variants develop and kidney and and and the of Alport the individuals with heterozygous COL4A3 or COL4A4 are to the those at risk of of the of ESKF and COL4A3 and COL4A4 and the and that the and and the of the basement in the and and of all the pathogenic variants in COL4A3 and COL4A4 are in the loss of the of and of and Alport pathogenic features and of variants are and the are of are but have been to as pathogenic are often pathogenic COL4A3 or COL4A4 variants in the of in Alport that of the are affected with and of are with has that is of all the and is heterozygous variants of the COL4A3 or COL4A4 in of the of the basement membrane and the is in the is to of is in Alport syndrome to of basement to and to in is associated with the loss of the in and Alport and the of loss the and kidney of AD Alport syndrome that in to kidney of features and in dominant Alport syndrome in of individuals with AD Alport syndrome ESKF in and the in of of and features of basement membrane nephropathy COL4A3 or COL4A4 and features of dominant Alport of pathogenic variants in have at kidney Alport in and in largely the Alport in and in and Alport pathogenic features and of in Alport and features in individuals with Alport in Alport is Alport of in Alport with pathogenic variants has been to Alport and in and to Alport syndrome The in at kidney failure pathogenic heterozygous COL4A3 or COL4A4 variants and that are that with is risk and kidney and or kidney in and Alport pathogenic heterozygous COL4A3 and COL4A4 variants to kidney these are and to in in of heterozygous in the associated with and to and kidney in with and kidney in basement membrane with and kidney pathogenic heterozygous variants in COL4A3 or COL4A4 are associated with kidney The of and basement membrane in and and in and heterozygous pathogenic variants occur often to and the variants in the affected in Alport syndrome and with kidney of Alport as that pathogenic heterozygous COL4A3 or COL4A4 variants are uncommonly associated with hearing and ocular suggest that the term Alport syndrome” is implies the of used individuals with pathogenic heterozygous COL4A3 or COL4A4 the the all individuals with heterozygous pathogenic COL4A3 or COL4A4 have kidney and is and Alport pathogenic COL4A3 or COL4A4 variants are the in individuals with but affected individuals are to develop or have hearing loss or ocular are to the to as with and The to as well as to and to those The with kidney and the and of of of of Alport of the of and COL4A3 or COL4A4 of pathogenic COL4A3 variants in and Alport is is that the occurs in of with Alport and in of of Alport but are often of Alport pathogenic variants in individuals and AD Alport syndrome in the of to AD is and are that to AD the in of with and Alport syndrome with heterozygous pathogenic COL4A3 or COL4A4 have risk of ESKF with the and develop the typical Alport features of hearing loss or ocular these the of AD Alport syndrome is used and but ESKF and the or features are to COL4A3 or COL4A4 and the of and kidney and the of Alport the Alport syndrome is kidney hearing and ocular of and of the The of the term AD Alport syndrome has been individuals with heterozygous pathogenic COL4A3 or COL4A4 of of of the Alport implies these individuals develop as well as the features of hearing loss and ocular have and The risk of ESKF is AD Alport syndrome is The that all heterozygous COL4A3 or COL4A4 variants as AD Alport syndrome that condition occurs in of the of of of the Alport The to basement membrane and of have heterozygous pathogenic COL4A3 or COL4A4 variants in of of pathogenic COL4A3 variants in and Alport is the features of the of or kidney is AD Alport ESKF considered in studies of of membrane of of is associated with and basement membrane syndrome in features and of with and and of basement membrane The hearing loss membrane and the ocular as and in basement membrane and the of Alport syndrome and basement membrane features in Alport and and the pathogenic COL4A3 or COL4A4 have individuals with basement membrane basement membrane studies have to the of hearing loss and ocular defects with pathogenic heterozygous COL4A3 or COL4A4 of affected individuals in hearing loss in and ocular in of and features of basement membrane nephropathy COL4A3 or COL4A4 with individuals the typical hearing loss in and ocular features in and features of dominant Alport the hearing loss and ocular are with heterozygous pathogenic COL4A3 or COL4A4 in the of the hearing and of the ocular are typical of Alport syndrome and features have COL4A3 or COL4A4 and of these studies that of and of individuals with AD Alport syndrome of and features of basement membrane nephropathy COL4A3 or COL4A4 and features of dominant Alport are of 14% to of of COL4A3 and COL4A4 with kidney and features of dominant Alport in in of heterozygous in the associated with and to and kidney and failure in basement membrane has that AD and Alport syndrome are in the of pathogenic COL4A3 variants in and Alport and these studies have all been to have the to the risk of ESKF in of with AD Alport the of to variants is the in of kidney failure as in the studies have the of pathogenic and variants in with or kidney failure have studies have that heterozygous pathogenic COL4A3 and COL4A4 variants occur as often as pathogenic variants and kidney in Alport of in kidney to end-stage of and kidney in with kidney of kidney kidney of kidney in kidney end-stage kidney with the of and variants in the the of pathogenic COL4A4 and variants in the of kidney of pathogenic COL4A3 variants in and Alport pathogenic variants to and and variants that affected in the The of in and and with the of in kidney of membrane of heterozygous pathogenic COL4A3 or COL4A4 variants in in of the and pathogenic variants in in of pathogenic COL4A3 variants in and Alport pathogenic COL4A3 and COL4A4 variants as often as pathogenic variants in the and if of these is AD Alport syndrome occurs as often as Alport pathogenic COL4A3 and COL4A4 variants as to ESKF as as often in with kidney occur as that heterozygous pathogenic variants in COL4A3 and COL4A4 are to ESKF in ESKF in Alport with pathogenic have variants that are associated with or kidney variants are Alport syndrome to the in the is in and kidney failure in have Alport syndrome as often as of but are to develop kidney syndrome in and the that used to the of COL4A3 and COL4A4 to variants and and in the of pathogenic COL4A3 variants in and Alport have of pathogenic COL4A3 variants in and Alport used all the and is that of with pathogenic variants develop kidney failure the of and that is at the of Alport in and in Alport and in and to Alport syndrome of the with pathogenic variants are and of with have kidney failure features and of with and The risk of with pathogenic ESKF of as of with pathogenic are with risk of kidney failure the of the to kidney failure risk is the risk with pathogenic is the risk of with pathogenic ESKF the of is the of these or risk of kidney failure pathogenic COL4A3 or COL4A4 variants is that or is the risk of ESKF the of pathogenic COL4A3 or COL4A4 variants is and the of are to these heterozygous pathogenic COL4A3 or COL4A4 variants in The with kidney failure cited individuals with Alport features to have and have in in the of with pathogenic variants and with heterozygous COL4A3 or COL4A4 or variants are often and have the ESKF Alport in and in Alport and in and to Alport syndrome suggest that pathogenic variants the are and associated with kidney failure of but these the of heterozygous pathogenic COL4A3 or COL4A4 variants the of of kidney and of all the heterozygous variants in the COL4A3 and COL4A4 are and have risk of risk kidney and kidney Alport in and in and with kidney kidney and the of and kidney with pathogenic heterozygous COL4A3 or COL4A4 variants develop and kidney and and and the of Alport the individuals with heterozygous COL4A3 or COL4A4 are to the those at risk of of the of ESKF and COL4A3 and COL4A4 and the and that the and and the of the basement in the and and of all the pathogenic variants in COL4A3 and COL4A4 are in the loss of the of and of and Alport pathogenic features and of variants are and the are of are but have been to as pathogenic are often pathogenic COL4A3 or COL4A4 variants in the of in Alport that of the are affected with and of are with has that is of all the and is heterozygous variants of the COL4A3 or COL4A4 in of the of the basement membrane and the is in the is to of is in Alport syndrome to of basement to and to in is associated with the loss of the in and Alport and the of loss the and kidney of AD Alport syndrome that in to kidney of features and in dominant Alport syndrome in of individuals with AD Alport syndrome ESKF in and the in of of and features of basement membrane nephropathy COL4A3 or COL4A4 and features of dominant Alport of pathogenic variants in have at kidney Alport in and in largely the Alport in and in and Alport pathogenic features and of in Alport and features in individuals with Alport in Alport is Alport of in Alport with pathogenic variants has been to Alport and in and to Alport syndrome The in at kidney failure pathogenic heterozygous COL4A3 or COL4A4 variants and that are that with is risk and kidney and or kidney in and Alport pathogenic heterozygous COL4A3 and COL4A4 variants to kidney these are and to in in of heterozygous in the associated with and to and kidney in with and kidney in basement membrane with and kidney pathogenic heterozygous variants in COL4A3 or COL4A4 are associated with kidney The of and basement membrane in and and in and heterozygous pathogenic variants occur often to and the variants in the affected in Alport syndrome and with kidney of Alport as that pathogenic heterozygous COL4A3 or COL4A4 variants are uncommonly associated with hearing and ocular suggest that the term Alport syndrome” is implies the of used individuals with pathogenic heterozygous COL4A3 or COL4A4 the the all individuals with heterozygous pathogenic COL4A3 or COL4A4 have kidney and is and Alport pathogenic COL4A3 or COL4A4 variants are the in individuals with but affected individuals are to develop or have hearing loss or ocular are to the to as with and The to as well as to and to those The with kidney and the and of of of of Alport of the of and COL4A3 or COL4A4 of pathogenic COL4A3 variants in and Alport is is that the occurs in of with Alport and in of of Alport but are often of Alport pathogenic variants in individuals and AD Alport syndrome in the of to AD is and are that to AD the in of with and Alport syndrome with heterozygous pathogenic COL4A3 or COL4A4 have risk of ESKF with the and develop the typical Alport features of hearing loss or ocular these the of AD Alport syndrome is used and but ESKF and the or features are to COL4A3 or COL4A4 and the of and kidney and the of Alport the in ESKF in Alport with pathogenic have variants that are associated with or kidney variants are Alport syndrome to the in the is in and kidney failure in have Alport syndrome as often as of but are to develop kidney syndrome in and the that used to the of COL4A3 and COL4A4 to variants and and in the of pathogenic COL4A3 variants in and Alport have of pathogenic COL4A3 variants in and Alport used all the and is that of with pathogenic variants develop kidney failure the of and that is at the of Alport in and in Alport and in and to Alport syndrome of the with pathogenic variants are and of with have kidney failure features and of with and The risk of with pathogenic ESKF of as of with pathogenic are with risk of kidney failure the of the to kidney failure risk is the risk with pathogenic is the risk of with pathogenic ESKF the of is the of these or risk of kidney failure pathogenic COL4A3 or COL4A4 variants is that or is the risk of ESKF the of pathogenic COL4A3 or COL4A4 variants is and the of with pathogenic have variants that are associated with or kidney variants are Alport syndrome to the in the is in and kidney failure in have Alport syndrome as often as of but are to develop kidney syndrome in and the that used to the of COL4A3 and COL4A4 to variants and and in the of pathogenic COL4A3 variants in and Alport have of pathogenic COL4A3 variants in and Alport used all the and is that of with pathogenic variants develop kidney failure the of and that is at the of Alport in and in Alport and in and to Alport syndrome of the with pathogenic variants are and of with have kidney failure features and of with and The risk of with pathogenic ESKF of as of with pathogenic are with risk of kidney failure the of the to kidney failure risk is the risk with pathogenic is the risk of with pathogenic ESKF the of is the of these or The risk of kidney failure pathogenic COL4A3 or COL4A4 variants is that or is the risk of ESKF the of pathogenic COL4A3 or COL4A4 variants is and the of are to these heterozygous pathogenic COL4A3 or COL4A4 variants in The with kidney failure cited individuals with Alport features to have and have in in the of with pathogenic variants and with heterozygous COL4A3 or COL4A4 or variants are often and have the ESKF Alport in and in Alport and in and to Alport syndrome suggest that pathogenic variants the are and associated with kidney failure are to these heterozygous pathogenic COL4A3 or COL4A4 variants in The with kidney failure cited individuals with Alport features to have and have in in the of with pathogenic variants and with heterozygous COL4A3 or COL4A4 or variants are often and have the ESKF Alport in and in Alport and in and to Alport syndrome suggest that pathogenic variants the are and associated with kidney failure of but these the of heterozygous pathogenic COL4A3 or COL4A4 variants the of of kidney and of all the heterozygous variants in the COL4A3 and COL4A4 are and have risk of risk kidney and kidney Alport in and in and with kidney kidney and the of and kidney with pathogenic heterozygous COL4A3 or COL4A4 variants develop and kidney and and and the of Alport the individuals with heterozygous COL4A3 or COL4A4 are to the those at risk of these the of heterozygous pathogenic COL4A3 or COL4A4 variants the of of kidney and of all the heterozygous variants in the COL4A3 and COL4A4 are and have risk of risk kidney and kidney Alport in and in and with kidney kidney and the of and kidney with pathogenic heterozygous COL4A3 or COL4A4 variants develop and kidney and and and the of Alport the individuals with heterozygous COL4A3 or COL4A4 are to the those at risk of of the of ESKF and COL4A3 and COL4A4 and the and that the and and the of the basement in the and and of all the pathogenic variants in COL4A3 and COL4A4 are in the loss of the of and of and Alport pathogenic features and of variants are and the are of are but have been to as pathogenic are often pathogenic COL4A3 or COL4A4 variants in the of in Alport that of the are affected with and of are with has that is of all the and is heterozygous variants of the COL4A3 or COL4A4 in of the of the basement membrane and the is in the is to of is in Alport syndrome to of basement to and to in is associated with the loss of the in and Alport and the of loss the and kidney of AD Alport syndrome that in to kidney of features and in dominant Alport syndrome in of individuals with AD Alport syndrome ESKF in and the in of of and features of basement membrane nephropathy COL4A3 or COL4A4 and features of dominant Alport of pathogenic variants in have at kidney Alport in and in largely the Alport in and in and Alport pathogenic features and of in Alport and features in individuals with Alport in Alport is Alport of in Alport with pathogenic variants has been to Alport and in and to Alport syndrome The in at kidney failure pathogenic heterozygous COL4A3 or COL4A4 variants and that are that with is risk and kidney and or kidney in and Alport pathogenic heterozygous COL4A3 and COL4A4 variants to kidney these are and to in in of heterozygous in the associated with and to and kidney in with and kidney in basement membrane with and kidney pathogenic heterozygous variants in COL4A3 or COL4A4 are associated with kidney The of and basement membrane in and and in and heterozygous pathogenic variants occur often to and the variants in the affected in Alport syndrome and with kidney The and the and that the and and the of the basement in the and and of all the pathogenic variants in COL4A3 and COL4A4 are in the loss of the of and of and Alport pathogenic features and of variants are and the are of are but have been to as pathogenic are often pathogenic COL4A3 or COL4A4 variants in the of in Alport that of the are affected with and of are with has that is of all the and is heterozygous variants of the COL4A3 or COL4A4 in of the of the basement membrane and the is in the is to of is in Alport syndrome to of basement to and to The in is associated with the loss of the in and Alport and the of loss the and kidney of AD Alport syndrome that in to kidney of features and in dominant Alport syndrome in The of individuals with AD Alport syndrome ESKF in and the in of of and features of basement membrane nephropathy COL4A3 or COL4A4 and features of dominant Alport of pathogenic variants in have at kidney Alport in and in largely the Alport in and in and Alport pathogenic features and of in Alport and features in individuals with Alport in Alport is Alport of in Alport with pathogenic variants has been to Alport and in and to Alport syndrome The in at kidney failure pathogenic heterozygous COL4A3 or COL4A4 variants and that are that with is risk and kidney and or kidney in and Alport pathogenic heterozygous COL4A3 and COL4A4 variants to kidney these are and to in in of heterozygous in the associated with and to and kidney in with and kidney in basement membrane with and kidney pathogenic heterozygous variants in COL4A3 or COL4A4 are associated with kidney The of and basement membrane in and and in and heterozygous pathogenic variants occur often to and the variants in the affected in Alport syndrome and with kidney of Alport as that pathogenic heterozygous COL4A3 or COL4A4 variants are uncommonly associated with hearing and ocular suggest that the term Alport syndrome” is implies the of that pathogenic heterozygous COL4A3 or COL4A4 variants are uncommonly associated with hearing and ocular suggest that the term Alport syndrome” is implies the of used individuals with pathogenic heterozygous COL4A3 or COL4A4 the the all individuals with heterozygous pathogenic COL4A3 or COL4A4 have kidney and is and used individuals with pathogenic heterozygous COL4A3 or COL4A4 the the all individuals with heterozygous pathogenic COL4A3 or COL4A4 have kidney and is and Alport pathogenic COL4A3 or COL4A4 variants are the in individuals with but affected individuals are to develop or have hearing loss or ocular are to the to as with and The to as well as to and to those The with kidney and the and of pathogenic COL4A3 or COL4A4 variants are the in individuals with but affected individuals are to develop or have hearing loss or ocular are to the to as with and The to as well as to and to those The with kidney and the and of of of of Alport of the of and COL4A3 or COL4A4 of pathogenic COL4A3 variants in and Alport is is that the occurs in of with Alport and in of of Alport but are often of Alport pathogenic variants in individuals and AD Alport syndrome in the of to AD is and are that to AD the in of with and Alport syndrome of the of and COL4A3 or COL4A4 of pathogenic COL4A3 variants in and Alport is is that the occurs in of with Alport and in of of Alport but are often of Alport pathogenic variants in individuals and AD Alport syndrome in the of to AD is and are that to AD the in of with and Alport syndrome with heterozygous pathogenic COL4A3 or COL4A4 have risk of ESKF with the and develop the typical Alport features of hearing loss or ocular these the of AD Alport syndrome is used and but ESKF and the or features are to COL4A3 or COL4A4 and the of and kidney and the of Alport the with heterozygous pathogenic COL4A3 or COL4A4 have risk of ESKF with the and develop the typical Alport features of hearing loss or ocular these the of AD Alport syndrome is used and but ESKF and the or features are to COL4A3 or COL4A4 and the of and kidney and the of Alport the

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