Abstract
BackgroundFocal and segmental glomerulosclerosis (FSGS) is a histologic pattern of injury that characterizes a wide spectrum of diseases. Many genetic causes have been identified in FSGS but even in families with comprehensive testing, a significant proportion remain unexplained.MethodsIn a family with adult-onset autosomal dominant FSGS, linkage analysis was performed in 11 family members followed by whole exome sequencing (WES) in 3 affected relatives to identify candidate genes.ResultsPathogenic variants in known nephropathy genes were excluded. Subsequently, linkage analysis was performed and narrowed the disease gene(s) to within 3% of the genome. WES identified 5 heterozygous rare variants, which were sequenced in 11 relatives where DNA was available. Two of these variants, in LAMA2 and LOXL4, remained as candidates after segregation analysis and encode extracellular matrix proteins of the glomerulus. Renal biopsies showed classic segmental sclerosis/hyalinosis lesion on a background of mild mesangial hypercellularity. Examination of basement membranes with electron microscopy showed regions of dense mesangial matrix in one individual and wider glomerular basement membrane (GBM) thickness in two individuals compared to historic control averages.ConclusionsBased on our findings, we postulate that the additive effect of digenic inheritance of heterozygous variants in LAMA2 and LOXL4 leads to adult-onset FSGS. Limitations to our study includes the absence of functional characterization to support pathogenicity. Alternatively, identification of additional FSGS cases with suspected deleterious variants in LAMA2 and LOXL4 will provide more evidence for disease causality. Thus, our report will be of benefit to the renal community as sequencing in renal disease becomes more widespread.
Highlights
Focal and segmental glomerulosclerosis (FSGS) is a histologic pattern of injury that characterizes a wide spectrum of diseases
Defects in basement membrane proteins of the kidney such as those encoded by type IV collagen and LAMβ2 are amongst the monogenic causes of FSGS [1, 2]
Reports over the past several years have identified an under-recognition of pathogenic variants in type IV collagen, causative for Alport syndrome, in patients presenting with a range of phenotypes spanning from non-progressive haematuria/ albuminuria, adult-onset FSGS and classic disease [4,5,6,7]
Summary
Focal and segmental glomerulosclerosis (FSGS) is a histologic pattern of injury that characterizes a wide spectrum of diseases. Focal and segmental glomerulosclerosis (FSGS) is a histologic lesion with varied causes which include putative circulating factor(s), monogenic etiologies and hyperfiltering conditions [1, 2]. Defects in basement membrane proteins of the kidney such as those encoded by type IV collagen and LAMβ2 are amongst the monogenic causes of FSGS [1, 2]. Reports over the past several years have identified an under-recognition of pathogenic variants in type IV collagen, causative for Alport syndrome, in patients presenting with a range of phenotypes spanning from non-progressive haematuria/ albuminuria, adult-onset FSGS and classic (severe) disease [4,5,6,7]. Our own local experience has highlighted a preponderance of undiagnosed Alport syndrome but here we describe
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