Retinal Features of Family Members With Familial Exudative Vitreoretinopathy Caused By Mutations in KIF11 Gene

Abstract

Purpose To determine the clinical characteristics of patients and family members with familial exudative vitreoretinopathy (FEVR) caused by mutations in the KIF11 gene. Methods Twenty-one patients from 10 FEVR families with mutations in the KIF11 gene were studied. The retinal and systemic features were examined. The genetic analyses performed included Sanger sequencing of the KIF11 gene, whole exome sequencing, as well as array comparative genomic hybridization (CGH) analysis and multiple ligation probe assay (MLPA). Results Sequence analysis revealed seven different KIF11 mutations. Array CGH with MLPA revealed two different exon deletions. All probands had advanced FEVR with retinal detachments (RDs) and microcephaly with or without developmental disabilities. Patients with bilateral RDs were more frequently associated with developmental disabilities ( P = 0.023). Multimodal imaging of the family members revealed that six of nine patients without RDs (66%) had varying degrees of chorioretinopathy. The retinal folds in FEVR patients were associated with severe retinal avascularization. However, funduscopic changes in the peripheral retina were unremarkable in family members without RDs. A score representing the peripheral vascular anomalies determined from the fluorescein angiograms was lower than that of control eyes of patients with mutations of the Wnt signaling genes ( P = 0.0029). Conclusions The probands with KIF11 mutations were associated with severe ocular and systemic pathologies, whereas affected family members showed highly variable clinical manifestations. Peripheral vascular anomalies can often be unremarkable in eyes without RDs. Translational Relevance These findings highlight more diverse mechanisms that underlie the pathological changes in patients with FEVR.

Phenotype-Based Genetic Analysis Reveals Missing Heritability of KIF11-Related Retinopathy: Clinical and Genetic Findings

“…In line with previous observations [3,6,15,17], the six novel KIF11 variants included only one missense variant; the remaining five were either nonsense or frameshift small indels or variants affecting splicing. DIV c.1875+42A>G, described here, is the first DIV identified in the KIF11 gene.…”

“…The majority of KIF11 variants are truncating variants, such as nonsense and frameshift indels, and they introduce a premature termination codon (PTC) that causes premature protein truncation and triggers a nonsense-mediated decay (NMD) process. Several recent studies have detected copy number variants (CNVs) in patients with FVER [15][16][17]. Taken together, these findings indicate that most KIF11 variants cause KIF11-associated retinopathy through a loss of function mechanism.…”

Ocular Features Associated With Mutations in Atoh7 Gene Overlap Those With Familial Exudative Vitreoretinopathy

“…Familial exudative vitreoretinopathy is characterized by not only an avascular retina, but also abnormal vascular changes in the periphery such as the presence of multiple branches, anastomoses, V-shaped notches, and numerous branching of the peripheral vascular endings. 10 It is unclear whether the patients had the vascular pattern of FEVR. In this study, the fluorescein angiographic findings of the left eye of Case 2 were highly specific to FEVR.…”

“…A score for the vascular anomalies in the periphery for the diagnosis of FEVR was high at 10 of 12 points. 10…”

Whole exome sequencing revealed 14 variants in NDP, FZD4, LRP5, and TSPAN12 genes for 20 families with familial exudative vitreoretinopathy

“…FEVR can be inherited in autosomal dominant, autosomal recessive, or X-linked manners; the most common mode of inheritance is autosomal dominant [ 8 ]. Thus far, the following eleven genes have been reported to cause FEVR: norrin ( NDP , OMIM, 300658) [ 9 ], frizzled 4 ( FZD4 , OMIM, 604579) [ 10 ], low density lipoprotein receptor-related protein 5 ( LRP5 , OMIM, 603506) [ 11 ], tetraspanin 12 ( TSPAN12 , OMIM, 613310) [ 12 ], catenin beta 1 ( CTNNB1 , OMIM, 116806) [ 13 ], zinc finger protein 408 ( ZNF408 , OMIM, 616454) [ 14 ], atonal homolog 7 ( ATOH7 , OMIM, 609875) [ 15 ], kinesin family member 11 ( KIF11 , OMIM, 148760) [ 16 ], RCC1 and BTB domain containing protein 1 ( RCBTB1 , OMIM, 607867) [ 17 ], jagged 1 ( JAG1 , OMIM, 601920) [ 18 ], and α-catenin ( CTNNA1 , OMIM) [ 19 ]. Moreover, one locus, EVR3, which maps to 11p13-p12, can also lead to FEVR; its causative gene has not been fully identified [ 20 ].…”