Exome-wide burden analysis of rare variants in individuals with thin basement membrane nephropathy

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Thin basement membrane nephropathy (TBMN) is the most prevalent cause for microscopic hematuria (MH) and has a frequency of 1% in the general population. It is characterized by persistent MH and minimal proteinuria, if any. Histologically, a uniforme thinning of the glomerular basement membrane (GBM) on electron microscopy of a renal biopsy specimen can be identified. The mature GBM is composed of a heterotrimer of alpha-chains 3, 4 and 5 of type IV collagen encoded by genes COL4A3, COL4A4, COL4A5, respectively. In about 40% of TBMN cases, a single heterozygous pathogenic variant in COL4A3/COL4A4 can be identified. TBMN features an autosomal dominant inheritance pattern with reduced penetrance. Nonetheless, in one study featuring 13 Cypriot families with TBMN, about 40% of individuals with a heterozygous pathogenic variant in COL4A3/COL4A4 developed chronic kidney disease and about 20% progressed to end-stage renal disease. Moreover, individuals with TBMN carrying a heterozygous pathogenic COL4A3/COL4A4 variant can develop focal segemental glomerulosclerosis over time. Hence, TBMN is not a benign familial hematuric disease. Genetic data on TBMN comes from analysis of the genes COL4A3/COL4A4 and sequencing of specific single-nucleotide polymorphisms and not from unbiased exome-/genome-wide rare variant burden analyses. In comparison to TBMN, Alport syndrome (AS) is a clear-cut high-penetrance monogenic MH leading to progressive renal failure, pathognomonic changes on kidney biopsy and, frequently, extrarenal features like bilateral high-frequency sensorineural hearing loss and ocular changes such as anterior lenticonus. Biallelic pathogenic variants in COL4A3 and COL4A4 are associated with autosomal recessive AS (about 15% of AS) and hemizygous pathogenic variants in the gene COL4A5 with X-linked AS.The aim of this study is to perform exome sequencing in 300 individuals without suspicion of AS but with clinically-ascertained TBMN in order to conduct an exome-wide burden analysis of rare variants compared to 20,000 control exomes (already available; Munich Exome Server).This study will provide answers to the question in which genes rare coding non-synonymous variants are enriched in TBMN along with odds ratio calculations of rare variant burden. This data is important for genetic counselling and clinical management of individuals with TBMN and may give further insights in the genetic architecture of TBMN and hematuric glomerular disease in general. The study will be the first of its kind in TBMN research, a disorder common in the general population with a high economic impact.