DO: 0110025;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q25 | {Macular degeneration, age-related, 13, susceptibility to} | 615439 | Autosomal dominant | 3 | CFI | 217030 |
A number sign (#) is used with this entry because of evidence that susceptibility to age-related macular degeneration-13 (ARMD13) is conferred by heterozygous mutation in the CFI gene (217030) on chromosome 4q25.
Age-related macular degeneration (ARMD) is a multifactorial disorder of the central retina that is the most prevalent cause of progressive vision loss in the developed world. As in other chronic age-related diseases, most cases result from interplay between multiple environmental and genetic factors, with a resultant spectrum of phenotypes. In rare cases, ARMD may manifest early, but there is an exponential rise in prevalence after the age of 60 years (summary by Pras et al., 2015).
For a phenotypic description and a discussion of genetic heterogeneity of age-related macular degeneration (ARMD), see 603075.
Pras et al. (2015) studied 2 Tunisian Jewish families in which affected individuals manifested a severe, highly penetrant phenotype of early-onset macular degeneration, with retinal pathologies that were indistinguishable from common ARMD, and high rates of advancement to blindness at senility. In the first family, 2 Tunisian Jewish sisters with ARMD, aged 66 and 68 years, showed distinct mechanisms of macular destruction and vision loss. One sister developed choroidal neovascularization that responded poorly to treatment, whereas the other sister showed progressive retinal pigment epithelium (RPE) loss and geographic atrophy, with surrounding well-defined hard drusen. Neither sister smoked; however, exome analysis (see MOLECULAR GENETICS) revealed differences in genetic background that might account for their disparate features. An unrelated 24-year-old Tunisian Jewish man, who presented with a conjunctival foreign body, was found on examination to have widespread intermediate ARMD, with multiple small foveal drusen and larger confluent drusen temporally. His affected mother and 3 of her sibs, who were in their fifth and sixth decades of life, showed dry (nonneovascular) ARMD with features that were less prominent than those of the proband. His maternal grandmother, who was blind at age 74, exhibited a wet (exudative) form of ARMD. Pras et al. (2015) noted that the proband had a 10-year history of smoking, a well-established risk factor for ARMD, which might explain the early onset of his disease.
In a case-control study involving 1,228 unrelated Caucasian patients aged 60 years or older with dry or neovascular advanced age-related macular degeneration and 825 controls, Fagerness et al. (2009) analyzed 1,500 SNPs in complement pathway genes and previously studied regions of interest, and identified significant association with 2 SNPs on chromosome 4q25, rs13117504 and rs10033900 (p = 2.11 x 10(-7) and 6.46 x 10(-8), respectively); the 2-SNP haplotype showed slightly stronger association than either SNP alone (p = 1.18 x 10(-8)). No obvious functional variation was found in coding exons in linkage disequilibrium with the SNPs. Fagerness et al. (2009) concluded that these SNPs likely tag an undiscovered biologically relevant variant.
In 84 unrelated patients with ARMD, van de Ven et al. (2013) analyzed the candidate gene CFI (217030) and identified 2 heterozygous missense mutations: G119R (217030.0010) in 3 probands, and G188A in 1 proband and 3 affected family members. Neither mutation was found in 192 ancestry- and age-matched controls, and no coexisting mutations in CFH (134370) were detected in patients carrying the CFI G119R or G188A substitutions. The G188A mutation was not found in 809 unrelated ARMD cases; however, screening for the G119R variant in 1,014 ARMD cases and 711 controls revealed the variant in 11 additional cases but none of the controls, demonstrating strong association of the G119R variant with ARMD (p = 2.16 x 10(-4)). Genotyping for G119R in additional cases resulted in the variant being identified in an overall total of 20 of 3,567 cases versus only 1 of 3,937 controls, consistent with G119R conferring high risk for developing ARMD (odds ratio, 22.20; p = 3.79 x 10(-6)). Van de Ven et al. (2013) noted that most carriers of the G119R variant had stage 4 ARMD. The 1 control carrying the minor allele had numerous hard drusen in all 4 quadrants of the peripheral retina but a normal macula in both eyes. Van de Ven et al. (2013) also noted that the G119R variant had previously been reported in patients with atypical hemolytic uremia syndrome (AHUS3; 612923) (Maga et al., 2010; Fakhouri et al., 2010); however, although ARMD patients carrying the CFI G119R variant exhibited a mild subclinical decrease in renal function, there was no significant difference in renal function of ARMD patients with G119R compared to ARMD patients without G119R.
Seddon et al. (2013) sequenced the exons of 681 genes within all reported ARMD loci and related pathways in 2,493 cases. First, each gene was tested for increased or decreased burden of rare variants in cases compared to controls. Seddon et al. (2013) found that 7.8% of ARMD cases compared to 2.3% of controls were carriers of rare missense CFI variants (odds ratio = 3.6; p = 2 x 10(-8)). There was a preponderance of dysfunctional variants in cases compared to controls. Seddon et al. (2013) then tested individual variants for association with disease.
To evaluate the functional impact of rare variants in the CFI gene, Kavanagh et al. (2015) measured circulating serum factor I (FI) protein levels in individuals with and without rare CFI variants. They observed that individuals with advanced ARMD carrying a rare CFI variant had lower mean FI than controls carrying a variant (p less than 0.001), and that individuals with a CFI rare variant and low FI were more likely to have advanced ARMD (p = 5.6 x 10(-5)). Controlling for covariates, low FI increased the risk of advanced ARMD among those with a variant compared to carrier individuals without advanced ARMD (OR 13.6; p = 1.6 x 10(-4)) and compared to controls without a rare CFI variant (OR 19.0; p = 1.1 x 10(-5)).
By whole-exome sequencing of 2 Tunisian Jewish sisters with ARMD, Pras et al. (2015) identified heterozygosity for a missense mutation in the CFI gene (V412M; 217030.0011) that segregated with disease in the family. Screening of 12 unrelated Tunisian patients with ARMD identified another carrier of the V412M mutation, a 24-year-old Jewish man; the mutation segregated fully with ARMD in his family as well. Analysis of 200 unrelated Tunisian Jewish controls identified 10 heterozygotes, for an estimated carrier frequency of 5% in that population. linkage analysis for V412M and ARMD in the 2 families yielded a lod score of 2.51 (theta = 0), strongly suggesting the CFI mutation as the cause of disease. Because the 2 affected sisters from the first family exhibited distinct mechanisms of macular destruction, with 1 showing choroidal neovascularization and the other geographic atrophy of the RPE, Pras et al. (2015) compared their exome data and identified some genetic background differences, including disparity in the ARMS2 gene (611313): the sister who developed CNV exclusively carried 2 heterozygous ARMS2 changes, R38X (rs2736911) and A69S (rs10490924; 611313.0001). The authors noted that the latter variant is regarded as an established risk factor for the wet form of ARMD.
Fagerness, J. A., Maller, J. B., Neale, B. M., Reynolds, R. C., Daly, M. J., Seddon, J. M. Variation near complement factor I is associated with risk of advanced AMD. Europ. J. Hum. Genet. 17: 100-104, 2009. [PubMed: 18685559] [Full Text: https://doi.org/10.1038/ejhg.2008.140]
Fakhouri, F., Roumenina, L., Provot, F., Sallee, M., Caillard, S., Couzi, L., Essig, M., Ribes, D., Dragon-Durey, M.-A., Bridoux, F., Rondeau, E., Fremeaux-Bacchi, V. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J. Am. Soc. Nephrol. 21: 859-867, 2010. [PubMed: 20203157] [Full Text: https://doi.org/10.1681/ASN.2009070706]
Kavanagh, D., Yu, Y., Schramm, E. C., Triebwasser, M., Wagner, E. K., Raychaudhuri, S., Daly, M. J., Atkinson, J. P., Seddon, J. M. Rare genetic variants in the CFI gene are associated with advanced age-related macular degeneration and commonly result in reduced serum factor I levels. Hum. Molec. Genet. 24: 3861-3870, 2015. [PubMed: 25788521] [Full Text: https://doi.org/10.1093/hmg/ddv091]
Maga, T. K., Nishimura, C. J., Weaver, A. E., Frees, K. L., Smith, R. J. H. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum. Mutat. 31: E1445-E1460, 2010. Note: Electronic Article. [PubMed: 20513133] [Full Text: https://doi.org/10.1002/humu.21256]
Pras, E., Kristal, D., Shoshany, N., Volodarsky, D., Vulih, I., Celniker, G., Isakov, O., Shomron, N., Pras, E. Rare genetic variants in Tunisian Jewish patients suffering from age-related macular degeneration. J. Med. Genet. 52: 484-492, 2015. [PubMed: 25986072] [Full Text: https://doi.org/10.1136/jmedgenet-2015-103130]
Seddon, J. M., Yu, Y., Miller, E. C., Reynolds, R., Tan, P. L., Gowrisankar, S., Goldstein, J. I., Triebwasser, M., Anderson, H. E., Zerbib, J., Kavanagh, D., Souied, E., Katsanis, N., Daly, M. J., Atkinson, J. P., Raychaudhuri, S. Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nature Genet. 45: 1366-1370, 2013. [PubMed: 24036952] [Full Text: https://doi.org/10.1038/ng.2741]
van de Ven, J. P. H., Nilsson, S. C., Tan, P. L., Buitendijk, G. H. S., Ristau, T., Mohlin, F. C., Nabuurs, S. B., Schoenmaker-Koller, F. E., Smailhodzic, D., Campochiaro, P. A., Zack, D. J., Duvvari, M. R., and 13 others. A functional variant in the CFI gene confers a high risk of age-related macular degeneration. Nature Genet. 45: 813-817, 2013. [PubMed: 23685748] [Full Text: https://doi.org/10.1038/ng.2640]