Fuchs corneal dystrophy (FCD) is a genetic disorder of the corneal endothelium and is the most common cause of corneal transplantation in the United States. Previously, we mapped a late-onset FCD locus, FCD2, on chromosome 18q. Here, we present next-generation sequencing of all coding exons in the FCD2 critical interval in a multigenerational pedigree in which FCD segregates as an autosomal-dominant trait. We identified a missense change in LOXHD1, a gene causing progressive hearing loss in humans, as the sole variant capable of explaining the phenotype in this pedigree. We observed LOXHD1 mRNA in cultured human corneal endothelial cells, whereas antibody staining of both human and mouse corneas showed staining in the corneal epithelium and endothelium. Corneal sections of the original proband were stained for LOXHD1 and demonstrated a distinct increase in antibody punctate staining in the endothelium and Descemet membrane; punctate staining was absent from both normal corneas and FCD corneas negative for causal LOXHD1 mutations. Subsequent interrogation of a cohort of >200 sporadic affected individuals identified another 15 heterozygous missense mutations that were absent from >800 control chromosomes. Furthermore, in silico analyses predicted that these mutations reside on the surface of the protein and are likely to affect the protein's interface and protein-protein interactions. Finally, expression of the familial LOXHD1 mutant allele as well as two sporadic mutations in cells revealed prominent cytoplasmic aggregates reminiscent of the corneal phenotype. All together, our data implicate rare alleles in LOXHD1 in the pathogenesis of FCD and highlight how different mutations in the same locus can potentially produce diverse phenotypes.

The authors report the first independent replication of rs613872 conferring risk of late-onset FCD. Their data suggest that this risk factor is likely independent of the FCD2 locus, whose causality remains unknown.

Purpose To investigate the clinical and genetic features of late-onset FCD on Tangier, an island in the Chesapeake Bay with an isolated population of approximately 500 individuals. Design Observational, cross-sectional study Methods A total of 156 individuals born to inhabitants of Tangier Island volunteered to undergo ophthalmic evaluation. Medical history was ascertained prior to examination. All participants underwent anterior segment examination with slit-lamp biomicroscopy. Retroillumination photographs were acquired from affected individuals and the disease severity was compared with individuals from large families ascertained previously. Genomic DNA samples were investigated for the presence of the recently identified risk allele rs613872, an intronic variant of TCF4. Results Of the 148 examined individuals who were at least 30 years of age, 32 showed the classical symptoms of late-onset FCD (21.6%), providing a minimum prevalence of 11% among individuals over the age of 50 years. Severity was significantly lower compared to 51 cases from unlinked families, among individuals either 50 to 70 or above 70 years of age (p = 0.05 and 0.01, respectively). Retroillumination photography analyses were suggestive of mild severity when compared with the disease phenotype associated with FCD1 and FCD2-linked families. The rs613872 variant was associated with a higher affectation rate (p=0.01), while the wild-type allele was correlated with a higher proportion of subclinical disease (p=0.01). Conclusions In this study population in Tangier, late-onset FCD manifests clinically with a mild phenotype and increased prevalence. The rs613872 variant correlates with increased affectation and a clinical disease phenotype.

Purpose: To describe the efficacy and safety of open versus closed conjunctival implantation of the XEN45 Gel Stent (Allergan Inc). Design: Retrospective, multicenter study. Participants: A total of 137 patients with glaucoma who underwent XEN45 implantation via open or closed conjunctival methods. The XEN45 was implanted as a stand-alone procedure or at the time of cataract surgery by 5 surgeons. Methods: Patient demographics, diagnoses, preoperative and postoperative clinical data, outcome measures including intraocular pressure (IOP), use of glaucoma medications, visual acuity, and complications were collected. Statistical analyses were performed with P < 0.05 as significant. Main Outcome Measures: Failure was defined as less than 20% reduction of IOP from medicated baseline or IOP >21 mmHg at 2 consecutive visits at postoperative month 1 and beyond, the need for subsequent operative intervention or additional glaucoma surgery, or a catastrophic event such as loss of light perception. Eyes that had not failed by these criteria and were not on glaucoma medications were considered complete successes. Eyes that had not failed but required glaucoma medications were defined as qualified successes. Results: Complete success was achieved in 31% and 56% of the closed and open groups, respectively ( P = 0.01). Qualified success was achieved in 53% and 71% of the closed and open groups, respectively ( P = 0.06). At postoperative month 12, the open conjunctiva group was using fewer glaucoma medications than the closed group (0.9 vs. 1.8, respectively; P = 0.02). At postoperative month 12, the open group had a significantly greater percentage of IOP reduction compared with the closed group (43.1% vs. 24.8%, respectively; P = 0.02). Postoperative needling rates were higher in the closed group compared with the open group (36.1% vs. 11.8%, P = 0.001). Conclusions: Implantation of the XEN45 with opening of the conjunctiva is a safe and efficacious procedure to lower IOP with comparable success rate and lower needling rate compared with the closed conjunctiva technique. Prospective evaluation of the various methods for XEN45 implantation will allow for further comparison.