Rare Variants in Complement Gene in C3 Glomerulopathy and Immunoglobulin-Mediated Membranoproliferative GN

Background C3 glomerulopathy and idiopathic immunoglobulin-mediated membranoproliferative GN (Ig-MPGN) are rare complement-mediated kidney diseases. Inherited forms of C3 glomerulopathy/Ig-MPGN are rarely described. Methods Three hundred ninety-eight patients with C3 glomerulopathy (n-296) or Ig-MPGN (n-102) from a national registry were screened for three complement genes: factor H (CFH), factor I (CFI), and C3. Patients with rare variant (minor allele frequency,0.1%) were included. Epidemiologic, clinical, and immunologic data at diagnosis and kidney outcomes of patients were retrospectively collected. Results Fifty-three different rare variants, including 30 (57%), 13 (24%), and ten (19%) in CFH, CFI, and C3 variants, were identified in 66/398 (17%) patients. Thirty-eight (72%) variants were classified as pathogenic, including 20/30 (66%) and 11/13 (84%) variants in CFH and CFI, respectively, impairing synthesis of factor H or factor I regulators. Fifteen of 53 (27%) variants were of unknown significance. At diagnosis, 69% of patients were adult (median age of 31 years). With the exception of biologic stigma of thrombotic microangiopathy, which was more frequent in patients with CFI variants (5/14 [36%] versus 1/ 37 [3%] and 0% in the CFH group and C3 group, respectively, P < 0.001), the clinical and histologic features were similar among the three variants groups. The kidney outcome was poor regardless of the age at onset and treatment received. Sixty-five percent (43/66) of patients with rare variant reach kidney failure after a median delay of 41 (19-104) months, compared with 28% (55/195) after a median delay of 34 (12-143) months in the nonvariant group. Among 36 patients who received a kidney transplant, 2-year recurrence was frequent, occurring in 39% (12/31), without difference between variant groups, and led to graft failure in three cases. Conclusions In our cohort, 17% of C3 glomerulopathy/Ig-MPGN cases were associated with rare variants in the CFH, CFI, or C3 genes. In most cases, a quantitative deficiency in factor H or factor I was identified. The presence of a rare variant was associated with poor kidney survival.