Whole Exome Sequencing in Patients with the Cuticular Drusen Subtype of Age-Related Macular Degeneration

PLoS One. 2016 Mar 23;11(3):e0152047. doi: 10.1371/journal.pone.0152047. eCollection 2016.


Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in elderly people worldwide. Cuticular drusen (CD) is a clinical subtype of AMD, which typically displays an earlier age at onset, and has a strong genetic component. Genetic studies support a role for rare sequence variants in CD susceptibility, and rare sequence variants in the CFH gene have been identified in 8.8% of CD cases. To further explore the role of rare variants in CD, we performed whole exome sequencing (WES) in 14 affected members of six families and 12 sporadic cases with CD. We detected rare sequence variants in CFH and FBLN5, which previously were shown to harbor rare variants in patients with CD. In addition, we detected heterozygous rare sequence variants in several genes encoding components of the extracellular matrix (ECM), including FBLN1, FBLN3/EFEMP1, FBLN5, FBLN6/HMCN1, FBN2, and COL15A1. Two rare pathogenic variants were identified in the COL15A1 gene: one in a sporadic case and another was found to segregate in a family with six affected individuals with CD. In addition, two rare pathogenic variants were identified in the FGL1 gene in three unrelated CD cases. These findings suggest that alterations in the ECM and in the coagulation pathway may play a role in the pathogenesis of CD. The identified candidate genes require further analyses in larger cohorts to confirm their role in the CD subtype of AMD. No evidence was found of rare sequence variants in a single gene that segregate with CD in the six families, suggesting that the disease is genetically heterogeneous.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Complement Factor H / genetics
  • Exome / genetics
  • Extracellular Matrix / genetics
  • Extracellular Matrix Proteins / genetics
  • Female
  • Genetic Variation / genetics
  • Heterozygote
  • Humans
  • Macular Degeneration / genetics*
  • Male
  • Middle Aged
  • Mutation, Missense / genetics
  • Retinal Drusen / genetics*


  • Extracellular Matrix Proteins
  • FBLN5 protein, human
  • Complement Factor H

Grant support

This study was supported by the Netherlands Organization for Scientific Research (Vidi Innovational Research Award 016.096.309) and the Foundation Fighting Blindness USA (grant C-GE-0811-0548-RAD04). The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) / ERC grant agreement n. 310644 (MACULA).