1. Case report
A 59-year-old female with a family history of vision loss in her mother from age 50 due to presumed neovascular age-related macular degeneration (nAMD; Supplementary Material) presented with complaints of central vision loss for several years. Clinical examination disclosed extensive bilateral confluent macular drusen (Fig. 1A and B). Macular OCT imaging revealed large drusenoid pigment epithelial detachments (PEDs) with overlying fluid (Fig. 1C and E), though no neovascularization was seen on intravenous angiography. Her vision progressively worsened over 4 years (Fig. 1D and F) with collapse of the PED and progression to atrophy on the left eye. Her 54-year-old sister had essentially identical findings (Fig. 1H and I). Whole exome sequencing (NovogeneAIT Genomics, Singapore; CLIA certified) disclosed a heterozygous loss-of function variant in CFH(NM_000186.4):c.55G > T p.(Glu19Ter), which was confirmed on Sanger targeted sequencing. The variant is likely pathogenic by ACMG criteria, with PVS1 very strong and PM2 supporting, with in silico scores of 0.625 (pathogenic very strong) on BayesDel addAF1 and 33 (pathogenic strong) on CADD.2 The variant was present in the patient and her sister, as well as two of the patient's children (see Fig. 1G; III.2, aged 38 and III.3, aged 25) who had not manifested visible disease (Fig. 1G), although we could not exclude the possibility that they were too young to have signs of EOMD, or whether the CFH variant was fully penetrant. The mother's personal history of retinal disease could be consistent with the autosomal dominant inheritance pattern observed for variants in this gene. The variant was novel, being absent from both local3 and international4 genomic databases, and was not present in the ClinVar database,5 indicating its extremely rare occurrence in the general population. All screened individuals had normal renal function, which was assessed in view of the risk of hemolytic uremia among individuals with CFH deficiency.6
Fig. 1.
[A–B] Fundus images of the affected proband, showing bilateral extensive confluent soft drusen with overlying lipid exudation and pigment. [C–F] Progression of macular degeneration on macular OCT with large PEDs, overlying EZ band degeneration, progression to atrophy on the left eye, and decline in BCVA in both eyes over 4 years. [G] Pedigree of the family with EOMD, showing individuals heterozygous for the CFH c.55G > T (p.E19X) variant (m). Whole exome sequencing outcomes were validated by targeted Sanger sequencing of the CFH c.55G > T variant. The proband is indicated with an arrow. [H–I] Fundus images and macular OCT of the proband's affected sister, with essentially identical findings of confluent macular drusen and large drusenoid PEDs.
2. Discussion
Early-onset macular drusen (EOMD) is a rare form of AMD that can be caused by CFH haploinsufficiency secondary to rare loss-of-function CFH variants.7,8 Unlike well-known AMD risk alleles such as CFH c.1204T > C (p.Y402H), which are common in the general population and confer only a modest risk of AMD,9,10 EOMD is caused by ultra-rare variants that more significantly impact CFH function and lead to higher penetrance disease that behaves more akin to inherited retinal disease (IRD) with multiple generations being affected.8 These rare variants may be accompanied by variably penetrant renal impairment, although surprisingly this was not observed in the current cases despite the N-terminal location of the variant. Previous reports have shown preserved renal function in patients with EOMD due to missense variants at codon 53,11 although our case appears to be the most N-terminal variant with EOMD and preserved renal function. Recently developed intravitreal complement inhibitors such as pegcetacoplan12 and avacincaptad pegol13 may represent an ideal treatment EOMD, while upcoming CFH gene augmentation therapies would also be expected to address CFH deficiency in affected individuals.
3. Conclusion
This case report highlights EOMD as a more severe and likely monogenic manifestation of typical AMD with early onset and significant impact upon affected family members. Clinicians should consider the diagnosis of EOMD in younger individuals (<60 yrs) presenting with drusen and a positive family history and arrange prompt genetic testing and systemic review of affected individuals.
CRediT authorship contribution statement
Lisa M. George: Writing – review & editing, Writing – original draft, Methodology, Investigation, Formal analysis, Data curation. Mathur Ranjana: Writing – review & editing, Supervision, Resources, Methodology, Investigation. Mathieu Quinodoz: Writing – review & editing, Software, Resources, Methodology, Investigation, Formal analysis, Data curation. Rachael W.C. Tang: Project administration, Methodology, Investigation, Data curation. Weng Khong Lim: Software, Methodology, Investigation, Formal analysis. Noa G. Gilhar: Writing – review & editing, Resources, Methodology, Investigation. Saadia Z. Farooqui: Writing – review & editing, Resources, Methodology, Investigation. Carlo Rivolta: Supervision, Software, Resources, Methodology, Investigation, Formal analysis. Beau J. Fenner: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.
Patient consent
Consent to publish this case has been obtained from the patient in writing.
Authorship
All authors attest that they meet the current ICMJE criteria for Authorship.
Funding
This work was supported by a grant from the SingHealth Foundation (R1748/71/2020), and the Duke-NUS EYE ACP-PRISM Precision Medicine Initiative (05/FY2024/EX(SLP_FY2023)/204-A293(a) and 05/FY2024/EX(SLP)/204-A293(b)).
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
None.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.ajoc.2025.102408.
Appendix A. Supplementary data
The following is the supplementary data to this article:
References
- 1.Feng B.J. PERCH: a unified framework for disease gene prioritization. Hum Mutat. Mar 2017;38(3):243–251. doi: 10.1002/humu.23158. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Schubach M., Maass T., Nazaretyan L., Röner S., Kircher M. CADD v1.7: using protein language models, regulatory CNNs and other nucleotide-level scores to improve genome-wide variant predictions. Nucleic Acids Res. Jan 5 2024;52(D1):D1143–d1154. doi: 10.1093/nar/gkad989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Chan S.H., Bylstra Y., Teo J.X., et al. Analysis of clinically relevant variants from ancestrally diverse Asian genomes. Nat Commun. Nov 5 2022;13(1):6694. doi: 10.1038/s41467-022-34116-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Karczewski K.J., Francioli L.C., Tiao G., et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. May 2020;581(7809):434–443. doi: 10.1038/s41586-020-2308-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Landrum M.J., Lee J.M., Benson M., et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. Jan 4 2016;44(D1):D862–D868. doi: 10.1093/nar/gkv1222. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Coccia P.A., Alconcher L.F., Ferraris V., et al. Eculizumab as first-line treatment for patients with severe presentation of complement factor H antibody-mediated hemolytic uremic syndrome. Pediatr Nephrol. Apr 2025;40(4):1041–1047. doi: 10.1007/s00467-024-06530-2. [DOI] [PubMed] [Google Scholar]
- 7.de Breuk A., Heesterbeek T.J., Bakker B., et al. Evaluating the occurrence of rare variants in the complement factor H gene in patients with early-onset drusen maculopathy. JAMA Ophthalmol. Nov 1 2021;139(11):1218–1226. doi: 10.1001/jamaophthalmol.2021.4102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Taylor R.L., Poulter J.A., Downes S.M., et al. Loss-of-Function mutations in the CFH gene affecting alternatively encoded factor H-like 1 protein cause dominant early-onset macular Drusen. Ophthalmology. Oct 2019;126(10):1410–1421. doi: 10.1016/j.ophtha.2019.03.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Hageman G.S., Anderson D.H., Johnson L.V., et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. May 17 2005;102(20):7227–7232. doi: 10.1073/pnas.0501536102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Haines J.L., Hauser M.A., Schmidt S., et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. Apr 15 2005;308(5720):419–421. doi: 10.1126/science.1110359. [DOI] [PubMed] [Google Scholar]
- 11.Yu Y., Triebwasser M.P., Wong E.K., et al. Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration. Hum Mol Genet. Oct 1 2014;23(19):5283–5293. doi: 10.1093/hmg/ddu226. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Heier J.S., Lad E.M., Holz F.G., et al. Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials. Lancet. Oct 21 2023;402(10411):1434–1448. doi: 10.1016/s0140-6736(23)01520-9. [DOI] [PubMed] [Google Scholar]
- 13.Khanani A.M., Patel S.S., Staurenghi G., et al. Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial. Lancet. Oct 21 2023;402(10411):1449–1458. doi: 10.1016/s0140-6736(23)01583-0. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.