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Terri L Young, Stuart W. J. Tompson, Benjamin R. Thomson, Owen M. Siggs, Vachiranee Limviphuvadh, Kristina N. Whisenhunt, Janey L Wiggs, Jamie E Craig, Susan E. Quaggin, Francesca Pasutto; Loss of function variants in a new gene increase risk for primary congenital glaucoma with variable expressivity. Invest. Ophthalmol. Vis. Sci. 2016;57(12):800.
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© ARVO (1962-2015); The Authors (2016-present)
Primary congenital glaucoma (PCG) results from aqueous outflow system defects leading to high intraocular pressure (IOP), globe expansion, and optic nerve cupping. CYP1B1 mutations account for 15-20% of cases in ethnically diverse populations, with other associations of LTBP2, FOXC1 and MYOC variants. Recent reports of combined vascular and lymphatic tissue types in murine Schlemm's canal development implicate contributions of PROX1, TEK (ANGPT1 and 2 receptor), and VEGF. We used exome sequencing to identify novel PCG candidate genes in unsolved families.
An international multi-center cohort of 189 PCG families was assembled. All were Sanger sequenced and mutation negative for the 4 known PCG genes. Exome sequencing was performed on 105 families. Common and unrelated variants present in the ExAC public database and 119 internal control exomes, respectively, were filtered. Sanger sequencing validated candidate disease gene variants and identified further variants in 84 additional PCG families and 629 cases with later-onset glaucoma (JOAG/POAG). Using mouse lines containing doxycycline-induced knock-out (KO) alleles, animals lacking functional alleles were generated to model the human genotype.
Heterozygosity for 1 rare missense and 2 novel nonsense variants in the Angiopoietin-1 gene, ANGPT1, was identified in 3/189 unrelated PCG families. Heterozygosity for an additional novel nonsense and 2 novel missense variants was identified in 3/629 families with JOAG/POAG. The 3 missense variants are at evolutionarily well-conserved residues, and relatively tolerated by in silico prediction tools. However, the 3 nonsense changes represent true loss-of-function (LoF) alleles. The ExAC database contains only a single LoF ANGPT1 variant from more than 121,000 ‘normal’ alleles, indicating non-tolerance for LoF variation. Although KO mice homozygous for Angpt1 from E13.5 had no overt phenotype, combined homozygous deletion of both Angpt1 and Angpt2 genes at E16.5 led to raised IOP and defects in Schlemm's canal development.
We have identified mutations in ANGPT1 as a risk factor for PCG and later-onset forms of human glaucoma. This suggests a requirement for vigilant glaucoma screening in relatives of patients that carry an ANGPT1 mutation, as they may develop glaucoma in later years. This data also highlights a novel pathway in PCG pathogenesis.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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