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Exome sequencing and association analysis implicates extracellular matrix gene, FBN2 in early and late onset macular degenerations

Thursday, October 11, 2012 — Poster Session III

10:00 a.m. – Noon

Natcher Conference Center, Building 45



* FARE Award Winner


  • R. Ratnapriya
  • X. Zhan
  • R.N. Fariss
  • C.F. Chakarova
  • K.E. Branham
  • M.M. Campos
  • J.S. Friedman
  • M. Brooks
  • H.K. Rajasimha
  • M.A. Morrison
  • S.G. Jacobson
  • M.L. Klein
  • E.Y. Chew
  • D. Stambolian
  • M.M. DeAngelis
  • S.S. Bhattacharya
  • J.R. Heckenlively
  • G.R. Abecasis
  • et. al.
  • A. Swaroop


Macular dystrophies are characterized by progressive loss of central vision loss due to macular dysfunction and encompasses from monogenic early-onset to complex late-onset form like age-related macular degeneration (AMD) with considerable clinical and genetic heterogeneity. Using exome sequencing, we have identified a novel heterozygous segregating mutation, p.Glu1144Lys in FBN2 gene in a two-generation family with early onset dominant macular dystrophy. FBN2 encodes a cysteine-rich glycoprotein, which is a principal component of extracellular matrix (ECM). Sequencing of patients with maculopathies identified additional rare variants. Immunofluorescence studies in human and monkey eye localized FBN2 in Bruch’s membrane, choroid and sclera. Bruch’s membrane is multilayered structure between the choroid and retinal pigment epithelium, and extra¬cellular deposits within or adjacent to Bruch’s membrane are often clinically associated with AMD. This prompted us to explore whether common variants in FBN2 are associated with AMD. Our analysis revealed the association of a non-synonymous (Val965Ile) SNP, rs154001, with AMD in the analysis of 1988 cases and 2182 population matched controls (p value=1.03×10-4; odds ratio= 0.85). Taken together our results advocate the role of a novel ECM gene, FBN2 in macular pathogenesis and establish an important link between rare and common form of maculopathy.

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