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Rare mutations in complement factor H show contribution to early onset familial age-related macular degeneration (AMD).

A collaboration of research institutes, led by the Ophthalmic Epidemiology and Genetics Service, Tufts Medical Center, Boston, has published the findings of an analysis which identified four rare variants in the complement factor H (CFH) gene among patients whose AMD disease was unexplained by known variants of CFH. Using next generation sequencing (NGS) technologies the researchers identified highly penetrant gene variants that associated with advanced AMD in four separate families. The four rare loss-of-function variants are thought to result in haplo-insufficient protein levels, in respect of which, certain patients may benefit from treatment with factor H supplementation. The researchers also argue that incorporation of the variants into comprehensive diagnostic models may provide for more precise clinical management.


The association of inheritance with AMD has been well established with between 46% and 71% of symptomatic variance among twins being explained by genetic factors. Several genomic wide association studies (GWAS), and follow up meta-analyses, have logged multiple genetic variants in over 20 different genes, each demonstrating an association with AMD risk. Common variants in the CFH gene account for the disease in some families but fail to explain patterns of disease in other families with multiple affected members. Rare penetrant variants have also been uncovered which help to explain the epidemiology in some cohorts however, the current research project was designed to assess families with a high prevalence of AMD with an unexplained genetic etiology. Four independent families, with an apparent low AMD risk based on previously identified variants, showed a high frequency of drusen, an earlier age of onset and low serum factor H levels or deficient cofactor activity.


In the published results, the researchers identified a missense variant in two families with advanced AMD while two other families appeared to carry an essential splice site variant. All carriers appeared to have low serum factor H levels, especially carriers of the splice variant. The researchers concluded in their study that the rare variants helped to explain pathology and potentially may be useful in guiding clinical care in certain circumstances. The researchers commented that “growing evidence of the impact of rare variants may raise awareness in the clinic setting for high risk of disease in the families affected. Investigating the associated functional and phenotypic consequences of rare variants will further our understanding of their role and that of CFH in the pathophysiology of AMD, and may lead to innovative therapeutic techniques.”