Kidney Disease Associated With Mono-allelic COL4A3 and COL4A4 Variants: A Case Series of 17 Families
Mono-allelic variants in COL4A3 and COL4A4 (COL4A3/COL4A4) have been identified in a spectrum of glomerular basement membrane nephropathies, including thin basement membrane nephropathy and autosomal dominant Alport syndrome. With the increasing use of next generation sequencing, mono-allelic COL4A3...
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Veröffentlicht in: | Kidney medicine 2023-04, Vol.5 (4), p.100607-100607, Article 100607 |
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creator | Groen in ’t Woud, Sander Rood, Ilse M. Steenbergen, Eric Willemsen, Brigith Dijkman, Henry B. van Geel, Michel Schoots, Jeroen Wetzels, Jack F.M. Lugtenberg, Dorien Deegens, Jeroen K.J. Bongers, Ernie M.H.F. |
description | Mono-allelic variants in COL4A3 and COL4A4 (COL4A3/COL4A4) have been identified in a spectrum of glomerular basement membrane nephropathies, including thin basement membrane nephropathy and autosomal dominant Alport syndrome. With the increasing use of next generation sequencing, mono-allelic COL4A3/COL4A4 variants are detected more frequently, but phenotypic heterogeneity impedes counseling. We aimed to investigate the phenotypic spectrum, kidney biopsy results, and segregation patterns of patients with mono-allelic COL4A3/COL4A4 variants identified by whole exome sequencing.
Case series.
We evaluated clinical and pathologic characteristics of 17 Dutch index patients with mono-allelic variants in COL4A3/COL4A4 detected by diagnostic whole exome sequencing and 25 affected family members with variants confirmed by Sanger sequencing.
Eight different mono-allelic COL4A3/COL4A4 variants were identified across members of 11 families, comprising 7 glycine substituted missense variants and 1 frameshift variant. All index patients had microscopic hematuria at clinical presentation (median age 43 years) and 14 had (micro)albuminuria/proteinuria. All family members showed co-segregation of the variant with at least hematuria. At end of follow-up of all 42 individuals (median age 54 years), 16/42 patients had kidney function impairment, of whom 6 had kidney failure. Reports of kidney biopsies of 14 patients described thin basement membrane nephropathy, focal segmental glomerulosclerosis, minimal change lesions, and Alport syndrome. Electron microscopy images of 7 patients showed a significantly thinner glomerular basement membrane compared with images of patients with idiopathic focal segmental glomerulosclerosis and other hereditary glomerular diseases. No genotype-phenotype correlations could be established.
Retrospective design, ascertainment bias toward severe kidney phenotypes, and familial hematuria.
This study confirms the wide phenotypic spectrum associated with mono-allelic COL4A3/COL4A4 variants, extending from isolated microscopic hematuria to kidney failure with high intra- and interfamilial variability.
[Display omitted] |
doi_str_mv | 10.1016/j.xkme.2023.100607 |
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Case series.
We evaluated clinical and pathologic characteristics of 17 Dutch index patients with mono-allelic variants in COL4A3/COL4A4 detected by diagnostic whole exome sequencing and 25 affected family members with variants confirmed by Sanger sequencing.
Eight different mono-allelic COL4A3/COL4A4 variants were identified across members of 11 families, comprising 7 glycine substituted missense variants and 1 frameshift variant. All index patients had microscopic hematuria at clinical presentation (median age 43 years) and 14 had (micro)albuminuria/proteinuria. All family members showed co-segregation of the variant with at least hematuria. At end of follow-up of all 42 individuals (median age 54 years), 16/42 patients had kidney function impairment, of whom 6 had kidney failure. Reports of kidney biopsies of 14 patients described thin basement membrane nephropathy, focal segmental glomerulosclerosis, minimal change lesions, and Alport syndrome. Electron microscopy images of 7 patients showed a significantly thinner glomerular basement membrane compared with images of patients with idiopathic focal segmental glomerulosclerosis and other hereditary glomerular diseases. No genotype-phenotype correlations could be established.
Retrospective design, ascertainment bias toward severe kidney phenotypes, and familial hematuria.
This study confirms the wide phenotypic spectrum associated with mono-allelic COL4A3/COL4A4 variants, extending from isolated microscopic hematuria to kidney failure with high intra- and interfamilial variability.
[Display omitted]</description><identifier>ISSN: 2590-0595</identifier><identifier>EISSN: 2590-0595</identifier><identifier>DOI: 10.1016/j.xkme.2023.100607</identifier><identifier>PMID: 36925663</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Alport syndrome ; COL4A3/COL4A4 ; FSGS ; genotype-phenotype ; mono-allelic variants ; Original Research ; type IV collagen nephropathy ; whole exome sequencing</subject><ispartof>Kidney medicine, 2023-04, Vol.5 (4), p.100607-100607, Article 100607</ispartof><rights>2023 The Authors</rights><rights>2023 The Authors.</rights><rights>2023 The Authors 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c456t-d24387ce28e8b2b33452fc5f777c404dbda431326281b0c3d229ffc70b8cf403</citedby><cites>FETCH-LOGICAL-c456t-d24387ce28e8b2b33452fc5f777c404dbda431326281b0c3d229ffc70b8cf403</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10011433/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10011433/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,27929,27930,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36925663$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Groen in ’t Woud, Sander</creatorcontrib><creatorcontrib>Rood, Ilse M.</creatorcontrib><creatorcontrib>Steenbergen, Eric</creatorcontrib><creatorcontrib>Willemsen, Brigith</creatorcontrib><creatorcontrib>Dijkman, Henry B.</creatorcontrib><creatorcontrib>van Geel, Michel</creatorcontrib><creatorcontrib>Schoots, Jeroen</creatorcontrib><creatorcontrib>Wetzels, Jack F.M.</creatorcontrib><creatorcontrib>Lugtenberg, Dorien</creatorcontrib><creatorcontrib>Deegens, Jeroen K.J.</creatorcontrib><creatorcontrib>Bongers, Ernie M.H.F.</creatorcontrib><title>Kidney Disease Associated With Mono-allelic COL4A3 and COL4A4 Variants: A Case Series of 17 Families</title><title>Kidney medicine</title><addtitle>Kidney Med</addtitle><description>Mono-allelic variants in COL4A3 and COL4A4 (COL4A3/COL4A4) have been identified in a spectrum of glomerular basement membrane nephropathies, including thin basement membrane nephropathy and autosomal dominant Alport syndrome. With the increasing use of next generation sequencing, mono-allelic COL4A3/COL4A4 variants are detected more frequently, but phenotypic heterogeneity impedes counseling. We aimed to investigate the phenotypic spectrum, kidney biopsy results, and segregation patterns of patients with mono-allelic COL4A3/COL4A4 variants identified by whole exome sequencing.
Case series.
We evaluated clinical and pathologic characteristics of 17 Dutch index patients with mono-allelic variants in COL4A3/COL4A4 detected by diagnostic whole exome sequencing and 25 affected family members with variants confirmed by Sanger sequencing.
Eight different mono-allelic COL4A3/COL4A4 variants were identified across members of 11 families, comprising 7 glycine substituted missense variants and 1 frameshift variant. All index patients had microscopic hematuria at clinical presentation (median age 43 years) and 14 had (micro)albuminuria/proteinuria. All family members showed co-segregation of the variant with at least hematuria. At end of follow-up of all 42 individuals (median age 54 years), 16/42 patients had kidney function impairment, of whom 6 had kidney failure. Reports of kidney biopsies of 14 patients described thin basement membrane nephropathy, focal segmental glomerulosclerosis, minimal change lesions, and Alport syndrome. Electron microscopy images of 7 patients showed a significantly thinner glomerular basement membrane compared with images of patients with idiopathic focal segmental glomerulosclerosis and other hereditary glomerular diseases. No genotype-phenotype correlations could be established.
Retrospective design, ascertainment bias toward severe kidney phenotypes, and familial hematuria.
This study confirms the wide phenotypic spectrum associated with mono-allelic COL4A3/COL4A4 variants, extending from isolated microscopic hematuria to kidney failure with high intra- and interfamilial variability.
[Display omitted]</description><subject>Alport syndrome</subject><subject>COL4A3/COL4A4</subject><subject>FSGS</subject><subject>genotype-phenotype</subject><subject>mono-allelic variants</subject><subject>Original Research</subject><subject>type IV collagen nephropathy</subject><subject>whole exome sequencing</subject><issn>2590-0595</issn><issn>2590-0595</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNp9kU1P3DAQhq2qqCDgD3BAPvaSxR5_JFshVatt-RBbcSgqR8uxJ8VLElM7i8q_J6sAopeePPa87-vRPIQccTbjjOuT9ezvfYczYCDGB6ZZ-YHsgZqzgqm5-viu3iWHOa8ZYwBSay4_kV2h56C0FnvEXwXf4xP9FjLajHSRc3TBDujpbRju6I_Yx8K2LbbB0eX1Si4Etb2fSkl_2RRsP-QvdEGXW_9PTAEzjQ3lJT2zXWjH6wHZaWyb8fDl3Cc3Z99vlhfF6vr8crlYFU4qPRQepKhKh1BhVUMthFTQONWUZekkk772VgouQEPFa-aEB5g3jStZXblGMrFPvk6xD5u6Q--wH5JtzUMKnU1PJtpg_u304c78jo9m3B_nUogx4fNLQop_NpgH04XssG1tj3GTDVRKSlAgYJTCJHUp5pywefuHM7MlZNZmS8hsCZmJ0Gg6fj_hm-WVxyg4nQQ4rukxYDLZBewd-pDQDcbH8L_8Z6wtn6Q</recordid><startdate>20230401</startdate><enddate>20230401</enddate><creator>Groen in ’t Woud, Sander</creator><creator>Rood, Ilse M.</creator><creator>Steenbergen, Eric</creator><creator>Willemsen, Brigith</creator><creator>Dijkman, Henry B.</creator><creator>van Geel, Michel</creator><creator>Schoots, Jeroen</creator><creator>Wetzels, Jack F.M.</creator><creator>Lugtenberg, Dorien</creator><creator>Deegens, Jeroen K.J.</creator><creator>Bongers, Ernie M.H.F.</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>6I.</scope><scope>AAFTH</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20230401</creationdate><title>Kidney Disease Associated With Mono-allelic COL4A3 and COL4A4 Variants: A Case Series of 17 Families</title><author>Groen in ’t Woud, Sander ; Rood, Ilse M. ; Steenbergen, Eric ; Willemsen, Brigith ; Dijkman, Henry B. ; van Geel, Michel ; Schoots, Jeroen ; Wetzels, Jack F.M. ; Lugtenberg, Dorien ; Deegens, Jeroen K.J. ; Bongers, Ernie M.H.F.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c456t-d24387ce28e8b2b33452fc5f777c404dbda431326281b0c3d229ffc70b8cf403</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Alport syndrome</topic><topic>COL4A3/COL4A4</topic><topic>FSGS</topic><topic>genotype-phenotype</topic><topic>mono-allelic variants</topic><topic>Original Research</topic><topic>type IV collagen nephropathy</topic><topic>whole exome sequencing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Groen in ’t Woud, Sander</creatorcontrib><creatorcontrib>Rood, Ilse M.</creatorcontrib><creatorcontrib>Steenbergen, Eric</creatorcontrib><creatorcontrib>Willemsen, Brigith</creatorcontrib><creatorcontrib>Dijkman, Henry B.</creatorcontrib><creatorcontrib>van Geel, Michel</creatorcontrib><creatorcontrib>Schoots, Jeroen</creatorcontrib><creatorcontrib>Wetzels, Jack F.M.</creatorcontrib><creatorcontrib>Lugtenberg, Dorien</creatorcontrib><creatorcontrib>Deegens, Jeroen K.J.</creatorcontrib><creatorcontrib>Bongers, Ernie M.H.F.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Kidney medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Groen in ’t Woud, Sander</au><au>Rood, Ilse M.</au><au>Steenbergen, Eric</au><au>Willemsen, Brigith</au><au>Dijkman, Henry B.</au><au>van Geel, Michel</au><au>Schoots, Jeroen</au><au>Wetzels, Jack F.M.</au><au>Lugtenberg, Dorien</au><au>Deegens, Jeroen K.J.</au><au>Bongers, Ernie M.H.F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Kidney Disease Associated With Mono-allelic COL4A3 and COL4A4 Variants: A Case Series of 17 Families</atitle><jtitle>Kidney medicine</jtitle><addtitle>Kidney Med</addtitle><date>2023-04-01</date><risdate>2023</risdate><volume>5</volume><issue>4</issue><spage>100607</spage><epage>100607</epage><pages>100607-100607</pages><artnum>100607</artnum><issn>2590-0595</issn><eissn>2590-0595</eissn><abstract>Mono-allelic variants in COL4A3 and COL4A4 (COL4A3/COL4A4) have been identified in a spectrum of glomerular basement membrane nephropathies, including thin basement membrane nephropathy and autosomal dominant Alport syndrome. With the increasing use of next generation sequencing, mono-allelic COL4A3/COL4A4 variants are detected more frequently, but phenotypic heterogeneity impedes counseling. We aimed to investigate the phenotypic spectrum, kidney biopsy results, and segregation patterns of patients with mono-allelic COL4A3/COL4A4 variants identified by whole exome sequencing.
Case series.
We evaluated clinical and pathologic characteristics of 17 Dutch index patients with mono-allelic variants in COL4A3/COL4A4 detected by diagnostic whole exome sequencing and 25 affected family members with variants confirmed by Sanger sequencing.
Eight different mono-allelic COL4A3/COL4A4 variants were identified across members of 11 families, comprising 7 glycine substituted missense variants and 1 frameshift variant. All index patients had microscopic hematuria at clinical presentation (median age 43 years) and 14 had (micro)albuminuria/proteinuria. All family members showed co-segregation of the variant with at least hematuria. At end of follow-up of all 42 individuals (median age 54 years), 16/42 patients had kidney function impairment, of whom 6 had kidney failure. Reports of kidney biopsies of 14 patients described thin basement membrane nephropathy, focal segmental glomerulosclerosis, minimal change lesions, and Alport syndrome. Electron microscopy images of 7 patients showed a significantly thinner glomerular basement membrane compared with images of patients with idiopathic focal segmental glomerulosclerosis and other hereditary glomerular diseases. No genotype-phenotype correlations could be established.
Retrospective design, ascertainment bias toward severe kidney phenotypes, and familial hematuria.
This study confirms the wide phenotypic spectrum associated with mono-allelic COL4A3/COL4A4 variants, extending from isolated microscopic hematuria to kidney failure with high intra- and interfamilial variability.
[Display omitted]</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>36925663</pmid><doi>10.1016/j.xkme.2023.100607</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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source | DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
subjects | Alport syndrome COL4A3/COL4A4 FSGS genotype-phenotype mono-allelic variants Original Research type IV collagen nephropathy whole exome sequencing |
title | Kidney Disease Associated With Mono-allelic COL4A3 and COL4A4 Variants: A Case Series of 17 Families |
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