Genetic analysis of the complement pathway in C3 glomerulopathy.

Area of Science:

• Nephrology
• Genetics
• Immunology

Background:

• C3 glomerulopathy (C3G) often mimics membranoproliferative glomerulonephritis (MPGN).
• Uncontrolled complement alternative pathway (CAP) activation drives C3G pathogenesis.
• Genetic factors in the complement system are implicated, but a comprehensive profile, especially in Asia, is lacking.

Purpose of the Study:

• To conduct a comprehensive genetic screen of 11 CAP genes in sporadic C3G.
• To analyze genetic variants in dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) subtypes.
• To compare genetic findings with immune complex-mediated MPGN.

Main Methods:

• Targeted genomic enrichment and massively parallel sequencing were employed.
• 43 patients with C3G (10 DDD, 33 C3GN) and 24 with immune complex-mediated MPGN were studied.
• Candidate CAP genes were screened for variants.

Main Results:

• Four novel and 16 rare variants were identified; one was likely pathogenic, 19 of uncertain significance.
• Variants in CFH, CFI, CD46, and C3 genes were most common.
• Defective CAP control due to hereditary abnormalities was found in 50% of DDD, 27% of C3GN, and 17% of immune complex-mediated MPGN cases.

Conclusions:

• Accurate genetic screening advances C3G pathogenesis understanding.
• Pathogenicity classification of variants is vital for patient management, prognosis, and therapeutic decisions.
• Genetic screening provides critical insights into C3G, aiding clinical care.