Kidney Disease Associated With Mono-allelic COL4A3 and COL4A4 Variants: A Case Series of 17 Families

Sander Groen In 't Woud; Ilse M Rood; Eric Steenbergen; Brigith Willemsen; Henry B Dijkman; Michel van Geel; Jeroen Schoots; Jack F M Wetzels; Dorien Lugtenberg; Jeroen K J Deegens; Ernie M H F Bongers

doi:10.1016/j.xkme.2023.100607

Kidney Disease Associated With Mono-allelic COL4A3 and COL4A4 Variants: A Case Series of 17 Families

Kidney Med. 2023 Feb 1;5(4):100607. doi: 10.1016/j.xkme.2023.100607. eCollection 2023 Apr.

Affiliations

¹ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
² Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.
³ Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.
⁴ Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
⁵ Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.

Abstract

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.

Keywords: Alport syndrome; COL4A3/COL4A4; FSGS; genotype-phenotype; mono-allelic variants; type IV collagen nephropathy; whole exome sequencing.