Researchers identified rare germline variants of complement factor H (CFH) as being more highly represented in patients with paroxysmal nocturnal hemoglobinuria (PNH) than in control individuals in a recent study. Study findings were reported in the journal Blood.

“Patients bearing these CFH variants may respond differently to proximal complement inhibitors,” the study investigators explained in their report.

Patients included in this retrospective study had been enrolled in the French Registry of Marrow Failure Syndromes. They had received a diagnosis of PNH and had been treated with eculizumab for 6 or more months.

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Genomic DNA from the patients was analyzed by next-generation sequencing that was focused on CFH, CFI, MCP, and C3 genes. Data on any variants of these genes, in addition to outcomes, were evaluated in these patients as well as in individuals from 2 control groups, which included 80 healthy adults from France and data from a public dataset.

The primary study endpoint was transfusion dependence, characterized by more than 2 red blood cell (RBC) transfusion episodes over 6 months.

Genetic variants were screened in 84 patients with PNH, with 83 patients included in analyses of primary and secondary objectives. Among the patients with PNH, rare variants of these genes had frequencies of 10.7% for CFH, 3.6% for CFI, and 4.8% for C3.

The frequency of CFH variants was significantly higher than what was seen with the healthy control individuals (P =.02) and the level found in the public dataset (P <.001). CFI and C3 variants did not appear to be overrepresented in the patients with PNH. The investigators also considered 3 out of 8 rare variants of CFH to be pathogenic.

Overall, a univariate analysis showed that in the patients with PNH, being transfusion dependent at 6 months after starting eculizumab therapy was associated with having a rare germline CFH variant (75.7%), compared with having wild-type status (33.3%; P =.015).

The investigators also noted that 3 patients had pathogenic CFH variants and 1 patient had a pathogenic CFI variant. Among these patients with identified pathogenic variants, each was transfusion-dependent for 6 months.

The study had a median follow-up time of 5.8 years (95% CI, 5.2-7.3). Compared with wild type, rare germline variants of CFH appeared associated with worse event-free and failure-free survival. Of 9 patients with PNH who had CFH variants, 8 continued to receive transfusions, and 2 reportedly experienced thromboses.

“Screening for CFH variants may help clinicians understand the suboptimal response to terminal inhibition and possibly adapt treatment with new proximal complement inhibitors,” the study investigators concluded in their report.


Prata PH, Galimard JE, Sicre de Fontbrune F, et al. Rare germline complement factor H variants in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2023;141(15):1812-1816. doi:10.1182/blood.2022017019