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

BACKGROUND: C3 glomerulopathy and idiopathic immunoglobulin-mediated membranoproliferative glomerulonephritis (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 3 complement genes, factor H (CFH), factor I (CFI) and C3. Patients with rare variant (minor allele frequency <0.1%) were included. Epidemiological, clinical and immunological data at diagnosis and kidney outcomes of patients were retrospectively collected.

RESULTS: Fifty-three different rare variants including 30 (57%), 13 (24%) and 10 (19%) 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 on 53 (27%) variants were of unknown significance. At diagnosis, 69% of patients were adult (median age of 31 years). With the exception of biological stigma of thrombotic microangiopathy, which was more frequent in patients with CFI variants (5/14 (36%) vs 1/37 (3%) and 0% in CFH group and C3 group, p<0.001), the clinical and histological 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 end stage kidney disease after a median delay of 41 [19-104] months, compared to 28% (55/195) after a median delay of 34 [12-143] months in the non-variant group. Among 36 patients who received a kidney transplant, two years-recurrence was frequent, occurring in 39% (12/31), without difference between variants groups and led to graft failure in 3 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 the majority of cases, a quantitative deficiency in factor H or factor I is identified. The presence of a rare variant was associated with poor kidney survival.