Genetic Modifiers of Mendelian Monogenic Collagen IV Nephropathies in Humans and Mice

Abstract

Familial hematuria is a clinical sign of a genetically heterogeneous group of conditions, accompanied by broad inter- and intrafamilial variable expressivity. The most frequent condition is caused by pathogenic (or likely pathogenic) variants in the collagen-IV genes, COL4A3/A4/A5. Pathogenic variants in COL4A5 are responsible for the severe X-linked glomerulopathy, Alport syndrome (AS), while homozygous or compound heterozygous variants in the COL4A3 or the COL4A4 gene cause autosomal recessive AS. AS usually leads to progressive kidney failure before the age of 40-years when left untreated. People who inherit heterozygous COL4A3/A4 variants are at-risk of a slowly progressive form of the disease, starting with microscopic hematuria in early childhood, developing Alport spectrum nephropathy. Sometimes, they are diagnosed with benign familial hematuria, and sometimes with autosomal dominant AS. At diagnosis, they often show thin basement membrane nephropathy, reflecting the uniform thin glomerular basement membrane lesion, inherited as an autosomal dominant condition. On a long follow-up, most patients will retain normal or mildly affected kidney function, while a substantial proportion will develop chronic kidney disease (CKD), even kidney failure at an average age of 55-years. A question that remains unanswered is how to distinguish those patients with AS or with heterozygous COL4A3/A4 variants who will manifest a more aggressive kidney function decline, requiring prompt medical intervention. The hypothesis that a subgroup of patients coinherit additional genetic modifiers that exacerbate their clinical course has been investigated by several researchers. Here, we review all publications that describe the potential role of candidate genetic modifiers in patients and include a summary of studies in AS mouse models.

Keywords: Alport syndrome; COL4 nephropathies; focal segmental glomerulosclerosis; genetic modifiers; glomerular diseases; thin basement membrane nephropathy.

Figure 1

Schematic representation of the hypothesized modifier role of co-inherited DNA variants in patients who present with a more severe phenotype of the collagen IV nephropathy than normally anticipated. (The upper scenario) depicts the situation where the putative modifier on its own is absolutely benign, or hypomorphic, not conferring any symptom or disease feature (e.g., heterozygous NPHS2:p.Arg229Gln). (The lower scenario) depicts the situation where the putative modifier is accompanied with some features, usually very mild, and together, the primary disease-causing variant and the modifier better explain the clinical picture of the patient than each one alone. It is also understood that more than one candidate for genetic modifiers might co-exist, thereby recapitulating a situation where the full phenotype is the result of oligogenic inheritance. A variation of these scenarios is when the co-inherited genetic modifier is in a homozygous state (see the case of MYO1E variants described here) [32]. The red asterisk depicts the genetic variant, either the primary COL4A pathogenic variant or the genetic modifier.