Integration of Genetic Testing and Pathology for the Diagnosis of Adults with FSGS

Background and objectives FSGS and nephrotic syndrome studies have shown that single gene causes are more likely to be foundinpediatric cases than adults. Consequently, many studies have examinedlimitedgenepanels in largely pediatric cohorts. Design, setting, participants, & measurements Whole-exome sequencing was performed in adults with FSGS diagnosed between 1976 and 2017 in the Toronto GN Registry. An expanded panel of 109 genes linked to FSGS, glomerular basement membrane abnormalities, as well as causes of pediatric ESKD including congenital abnormalities of the kidney and urinary tract (CAKUT) and nephronophthisis, were examined. Results The cohort was composed of 193 individuals from 179 families. Nearly half (49%) developed ESKD at a mean age of 47617 years. The genetic diagnostic rate was 11%. Of definitely pathogenic variants, 55% were in COL4A(A3/A4/A5), 40% were inpodocyte genes, and5% were inCAKUTgenes. Many, butnot all individualswith COL4A definitely pathogenic variants had some evidence of glomerular basementmembrane abnormalities. The estimatedmean survival/age of kidney failure for individualswith COL4A definitely pathogenic variantswas 58 years (95% confidence interval, 49 to 69), far later thanwhat has been reported in the literature. Likely pathogenic variants were identified in an additional 9% of the cohort, with most in COL4A. Correlation with glomerular basement membrane morphology suggested a causal role for at least some of these likely pathogenic variants. Conclusions Evenwith an expanded gene panel, we find thatCOL4Adisorders are the leadingmonogenic cause in adults diagnosed with FSGS.