Kidney Disease Associated With Mono-allelic COL4A3 and COL4A4 Variants : A Case Series of 17 Families
© 2023 The Authors..
Rationale & Objective: 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.
Study Design: Case series.
Setting & Participants: 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.
Results: 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.
Limitations: Retrospective design, ascertainment bias toward severe kidney phenotypes, and familial hematuria.
Conclusions: 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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:5 |
|---|---|
| Enthalten in: |
Kidney medicine - 5(2023), 4 vom: 16. Apr., Seite 100607 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Groen In 't Woud, Sander [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Alport syndrome |
|---|
| Anmerkungen: |
Date Revised 18.03.2023 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.1016/j.xkme.2023.100607 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM354311735 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM354311735 | ||
| 003 | DE-627 | ||
| 005 | 20231226061935.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.xkme.2023.100607 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1180.xml |
| 035 | |a (DE-627)NLM354311735 | ||
| 035 | |a (NLM)36925663 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Groen In 't Woud, Sander |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Kidney Disease Associated With Mono-allelic COL4A3 and COL4A4 Variants |b A Case Series of 17 Families |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 18.03.2023 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2023 The Authors. | ||
| 520 | |a Rationale & Objective: 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 | ||
| 520 | |a Study Design: Case series | ||
| 520 | |a Setting & Participants: 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 | ||
| 520 | |a Results: 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 | ||
| 520 | |a Limitations: Retrospective design, ascertainment bias toward severe kidney phenotypes, and familial hematuria | ||
| 520 | |a Conclusions: 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Alport syndrome | |
| 650 | 4 | |a COL4A3/COL4A4 | |
| 650 | 4 | |a FSGS | |
| 650 | 4 | |a genotype-phenotype | |
| 650 | 4 | |a mono-allelic variants | |
| 650 | 4 | |a type IV collagen nephropathy | |
| 650 | 4 | |a whole exome sequencing | |
| 700 | 1 | |a Rood, Ilse M |e verfasserin |4 aut | |
| 700 | 1 | |a Steenbergen, Eric |e verfasserin |4 aut | |
| 700 | 1 | |a Willemsen, Brigith |e verfasserin |4 aut | |
| 700 | 1 | |a Dijkman, Henry B |e verfasserin |4 aut | |
| 700 | 1 | |a van Geel, Michel |e verfasserin |4 aut | |
| 700 | 1 | |a Schoots, Jeroen |e verfasserin |4 aut | |
| 700 | 1 | |a Wetzels, Jack F M |e verfasserin |4 aut | |
| 700 | 1 | |a Lugtenberg, Dorien |e verfasserin |4 aut | |
| 700 | 1 | |a Deegens, Jeroen K J |e verfasserin |4 aut | |
| 700 | 1 | |a Bongers, Ernie M H F |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Kidney medicine |d 2019 |g 5(2023), 4 vom: 16. Apr., Seite 100607 |w (DE-627)NLM303572787 |x 2590-0595 |7 nnns |
| 773 | 1 | 8 | |g volume:5 |g year:2023 |g number:4 |g day:16 |g month:04 |g pages:100607 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.xkme.2023.100607 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 5 |j 2023 |e 4 |b 16 |c 04 |h 100607 | ||