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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Kidney medicine 2023-04, Vol.5 (4), p.100607-100607, Article 100607
Hauptverfasser: 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.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 100607
container_issue 4
container_start_page 100607
container_title Kidney medicine
container_volume 5
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
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10011433</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S2590059523000110</els_id><sourcerecordid>2854425232</sourcerecordid><originalsourceid>FETCH-LOGICAL-c456t-d24387ce28e8b2b33452fc5f777c404dbda431326281b0c3d229ffc70b8cf403</originalsourceid><addsrcrecordid>eNp9kU1P3DAQhq2qqCDgD3BAPvaSxR5_JFshVatt-RBbcSgqR8uxJ8VLElM7i8q_J6sAopeePPa87-vRPIQccTbjjOuT9ezvfYczYCDGB6ZZ-YHsgZqzgqm5-viu3iWHOa8ZYwBSay4_kV2h56C0FnvEXwXf4xP9FjLajHSRc3TBDujpbRju6I_Yx8K2LbbB0eX1Si4Etb2fSkl_2RRsP-QvdEGXW_9PTAEzjQ3lJT2zXWjH6wHZaWyb8fDl3Cc3Z99vlhfF6vr8crlYFU4qPRQepKhKh1BhVUMthFTQONWUZekkk772VgouQEPFa-aEB5g3jStZXblGMrFPvk6xD5u6Q--wH5JtzUMKnU1PJtpg_u304c78jo9m3B_nUogx4fNLQop_NpgH04XssG1tj3GTDVRKSlAgYJTCJHUp5pywefuHM7MlZNZmS8hsCZmJ0Gg6fj_hm-WVxyg4nQQ4rukxYDLZBewd-pDQDcbH8L_8Z6wtn6Q</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2854425232</pqid></control><display><type>article</type><title>Kidney Disease Associated With Mono-allelic COL4A3 and COL4A4 Variants: A Case Series of 17 Families</title><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><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.</creator><creatorcontrib>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.</creatorcontrib><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><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>
fulltext fulltext
identifier ISSN: 2590-0595
ispartof Kidney medicine, 2023-04, Vol.5 (4), p.100607-100607, Article 100607
issn 2590-0595
2590-0595
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10011433
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
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-12T08%3A20%3A04IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Kidney%20Disease%20Associated%20With%20Mono-allelic%20COL4A3%20and%20COL4A4%20Variants:%20A%20Case%20Series%20of%2017%20Families&rft.jtitle=Kidney%20medicine&rft.au=Groen%20in%20%E2%80%99t%20Woud,%20Sander&rft.date=2023-04-01&rft.volume=5&rft.issue=4&rft.spage=100607&rft.epage=100607&rft.pages=100607-100607&rft.artnum=100607&rft.issn=2590-0595&rft.eissn=2590-0595&rft_id=info:doi/10.1016/j.xkme.2023.100607&rft_dat=%3Cproquest_pubme%3E2854425232%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2854425232&rft_id=info:pmid/36925663&rft_els_id=S2590059523000110&rfr_iscdi=true