Genome-wide Linkage Scan in Fuchs Endothelial Corneal Dystrophy

Fuchs endothelial corneal dystrophy (FECD) is a common progressive disorder of the corneal endothelium that becomes symptomatic with aging.1 It appears as guttae progressively form on Descemet’s membrane along with corneal edema and stromal clouding leading to impaired vision. FECD has been one of the main indications for corneal transplantation in many countries, including the United States,2 with the main treatment modality being a penetrating keratoplasty, until the advent of various types of endothelial keratoplasty. FECD typically becomes symptomatic during the fifth or sixth decade of life and predominantly affects women, who comprise three of four affected individuals.3 The pathogenesis of FECD remains unknown, but the corneal endothelial cells are arrested in the G1 phase of the cell cycle and do not undergo mitosis.4 During a normal state, the cornea is kept in a state of deturgescence by endothelial cell Na+/K+ ATPases that remove fluid from the stroma and by tight junctions between endothelial cells that limit fluid entry.1 This maintains the stroma’s ordered arrangement of collagen and with it, the transparency of the cornea. In states of low endothelial cell density, the loss of the endothelium’s barrier function causes corneal edema. Damage to the endothelial cell layer therefore results in irreparable tissue damage that necessitates endothelial or penetrating keratoplasty.1 It is well established that FECD can affect multiple family members and that several genetic factors underlie the development of the disorder.5 However, the use of genetic approaches to identify the genes underlying the development of FECD is complicated by the late onset of the disease, so that parents and even siblings of the proband are often unavailable for study. In addition, younger individuals in a family may not clinically exhibit the disease because they may not be old enough to manifest the disorder. The first progress toward identifying gene mutations associated with familial FECD was provided by a rare subtype of FECD characterized by onset in early childhood. Early-onset FECD was found to be caused by a missense mutation, Q455K, in the COL8A2 gene (MIM: 120252), which encodes for the α2 subtype of collagen VIII, a major component of Descemet’s membrane. Three other missense mutations within COL8A2—R155Q, R304Q, and R434H—were found in patients with late-onset FECD, but their role remains uncertain, as R155Q has the same frequency in normal controls.6 Another mutation in COL8A2, L450W, that is believed to be pathogenic has been detected in a family with atypical FECD.7,8 Although mutations in COL8A2 have been linked to early-onset FECD, to date, mutations in the COL8A2 gene have not been associated with the much more common late-onset FECD.9–11 Heterozygous single nucleotide polymorphisms in the SLC4A11 gene on chromosome 20 (20p13) have recently been detected in four Chinese and Indian patients with the common phenotype of FECD,12 but they contribute to only ∼5% of the genetic burden of the disease. Family-based studies have mapped late-onset FECD susceptibility loci to 13ptel-13q12.1313 and 18q21.2-q21.32,14 in one and three large multigenerational FECD families, respectively. However, to date, there have been no FECD genetic linkage studies involving a large number of affected families. In this study, we performed the first whole-genome linkage scan for late-onset FECD in 22 families (linkage panel IV; Illumina, Inc., San Diego, CA).