Type IV Collagen Variants in Patients With Polycystic Kidneys

Background: Gene panel and whole exome sequencing of patients with cystic kidney disease have led to the discovery of unexpected phenotypic heterogeneity of genetic kidney diseases. Mutations in type IV collagen genes (COL4A3/COL4A4/COL4A5) have long been recognized as the cause of Alport syndrome and thin basement membrane disease. More recently, type IV collagen mutations have also been associated with focal segmental glomerulosclerosis. Among patients clinically selected and submitted for genetic assessment of polycystic kidneys, we sought to compare the prevalence of type IV collagen mutations between those with and without a pathogenic PKD1 or PKD2 variant. Methods: 808 participants of the Ontario Polycystic Kidney Disease registry provided DNA samples for targeted gene panel sequencing. Sequencing results from PKD1, PKD2, COL4A3, COL4A4, and COL4A5 were analyzed here. Participant charts were reviewed to analyze their cystic phenotype and obtain measurements of total kidney volume and kidney function. Results: 34 participants had a suspected pathogenic rare variant in a type IV collagen gene with a median age of 49 (range 24 - 72). One male was hemizygous for a COL4A5 variant (p.P1517T), while the remaining variants were carriers of a heterozygous variant. Type IV collagen variants were more prevalent in patients who did not also have a PKD1 or PKD2 rare variant compared to those with them (31 out of 315 patients compared to 3 out of 493; P < 1 x 10-5). Of 31 type IV collagen variants without a PKD1 or PKD2 mutation 20 had atypical cystic distributions, 11 had a cystic appearance consistent with typical autosomal dominant polycystic kidney disease (ADPKD), and only 2 had a highrisk Mayo classification (class C or worse). 3 of 34 patients with a type IV collagen variant had reached an eGFR < 30 ml/min/1.73m2. Conclusions: In patients with polycystic kidneys and gene panel sequencing results, type IV collagen mutations were more common in those without a PKD1 or PKD2 mutation compared to those with them, suggesting type IV collagen mutations may be associated with a cystic phenotype. Both typical and atypical cystic imaging patterns were observed but generally smaller age- and height-adjusted kidney volumes were observed. Funding: Private Foundation Support, Clinical Revenue Support