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Original Investigation |

Phenotypic Overlap Between Familial Exudative Vitreoretinopathy and Microcephaly, Lymphedema, and Chorioretinal Dysplasia Caused by KIF11 Mutations ONLINE FIRST

Johane M. Robitaille, MD1,2,3; Roxanne M. Gillett, PhD3; Marissa A. LeBlanc, PhD3; Daniel Gaston, PhD3; Mathew Nightingale, HND3; Michael P. Mackley, BSc3; Sandhya Parkash, MD4; Julie Hathaway, MSc5; Aidan Thomas, MSc6; Anna Ells, MD7; Elias I. Traboulsi, MD8; Elise Héon, MD9; Mélanie Roy, MD10; Stavit Shalev, MD11; Conrad V. Fernandez, MD12; Christine MacGillivray, BSc13; Karin Wallace, BSc1,2; Somayyeh Fahiminiya, PhD14,15; Jacek Majewski, PhD14,15; Christopher R. McMaster, PhD16; Karen Bedard, PhD3
[+] Author Affiliations
1IWK Health Centre Eye Care Team, Halifax, Nova Scotia, Canada
2Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada
3Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
4Department of Pediatrics, Maritime Medical Genetics Service, Dalhousie University, Halifax, Nova Scotia, Canada
5Providence Health Care Heart Centre, St. Paul’s Hospital, Vancouver Coastal Health, Vancouver, British Columbia, Canada
6Maritime Medical Genetics Service, IWK Health Centre, Halifax, Nova Scotia, Canada
7Department of Surgery, University of Calgary, Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada
8Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
9Department of Ophthalmology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
10Réseau de santé Vitalité Health Network, Hôpital regional Chaleur Regional Hospital, Bathurst, New Brunswick, Canada
11Genetic Institute, Emek Medical Center, Afula, Rappaport School of Medicine, Technion, Haifa, Israel
12Department of Pediatrics, Pediatric Oncology, Dalhousie University, Halifax, Nova Scotia, Canada
13Department of Ophthalmology, Capital Health, Halifax, Nova Scotia, Canada
14Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
15Genome Quebec Innovation Center, Montreal, Quebec, Canada
16Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
JAMA Ophthalmol. Published online August 14, 2014. doi:10.1001/jamaophthalmol.2014.2814
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Importance  Retinal detachment with avascularity of the peripheral retina, typically associated with familial exudative vitreoretinopathy (FEVR), can result from mutations in KIF11, a gene recently identified to cause microcephaly, lymphedema, and chorioretinal dysplasia (MLCRD) as well as chorioretinal dysplasia, microcephaly, and mental retardation (CDMMR). Ophthalmologists should be aware of the range of presentations for mutations in KIF11 because the phenotypic distinction between FEVR and MLCRD/CDMMR portends management implications in patients with these conditions.

Objective  To identify gene mutations in patients who present with a FEVR phenotype and explore the spectrum of ocular and systemic abnormalities caused by KIF11 mutations in a cohort of patients with FEVR or microcephaly in conjunction with chorioretinopathy or FEVR.

Design, Setting, and Participants  Clinical data and DNA were collected from each participant between 1998 and 2013 from the clinical practices of ophthalmologists and clinical geneticists internationally. Twenty-eight FEVR probands with diagnoses made by the referring physician and without a known FEVR gene mutation, and 3 with microcephaly and chorioretinopathy, were included. At least 1 patient in each pedigree manifested 1 or more of the following: macular dragging, partial retinal detachment, falciform folds, or total retinal detachment.

Exposures  Whole-exome sequencing was conducted on affected members in multiplex pedigrees, and Sanger sequencing of the 22 exons of the KIF11 gene was performed on singletons. Clinical data and history were collected and reviewed.

Main Outcomes and Measures  Identification of mutations in KIF11.

Results  Four novel heterozygous KIF11 mutations and 1 previously published mutation were identified in probands with FEVR: p.A218Gfs*15, p.E470X, p.R221G, c.790-1G>T, and the previously described heterozygous p.R47X. Documentation of peripheral avascular areas on intravenous fluorescein angiography was possible in 2 probands with fibrovascular proliferation demonstrating phenotypic overlap with FEVR.

Conclusions and Relevance  Mutations in KIF11 cause a broader spectrum of ocular disease than previously reported, including retinal detachment. The KIF11 gene likely plays a role in retinal vascular development and mutations in this gene can lead to clinical overlap with FEVR. Cases of FEVR should be carefully inspected for the presence of microcephaly as a marker for KIF11-related disease to enhance the accuracy of the prognosis and genetic counseling.

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Figure 1.
Novel KIF11 Mutations

A-D, Location of novel KIF11 mutations with respect to the genomic organization of KIF11. Three of the novel mutations, KIF11 p.E470X (c.1408G>T), p.A218Gfs*15 (c.652DupG), and KIF11 c.790-1G>T, lead to a truncation of the KIF11 protein coding sequence. KIF11 c.790-1G>T alters an acceptor splice site. The mutation occurs in a nucleotide that is highly conserved across a variety of taxa. The mutation was evaluated for functional significance using the software CRYP-SKIP, and Spliceman. Both programs predicted that the mutation has a high probability of affecting splicing. The nonsynonymous KIF11 p.R221G (c.661 A>G) mutation segregated with the disease in a pedigree with 4 affected individuals. The mutation, located in the kinesin motor domain, was evaluated for functional significance using the software programs PolyPhen-2, PROVEAN, and SIFT. All programs predicted that the mutation is damaging. The mutation was absent in the 300 in-house exomes and the Exome Variant Server, as well as in 180 chromosomes from a random white population. E, Sequence comparison of the KIF11 protein demonstrating the evolutionary conservation of the mutated KIF11 arginine 221 residue across a variety of taxa.

Graphic Jump Location
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Figure 2.
Fundus Photographs and Intravenous Fluorescein Angiography (IVFA)

A, E470X proband: the right fundus shows peripheral atrophic changes inferotemporally and an area of mild elevation. The left fundus manifests an inferior peripheral area of chorioretinal atrophy with retinal pigment epithelium clumping. B, E470X sister: a peripheral retinal fold courses inferotemporally with areas of atrophy in the right eye and peripheral retinal pigmentary changes only on the left. C, A218Gfs*15 proband: fibrovascular tissue with retinal folds involving the macula was present in both eyes without evidence of chorioretinopathy typically seen in microcephaly,lymphedema, and chorioretinal dysplasia. Retinal pigment epithelial changes were evident in keeping with retinal detachment and ischemic stress. D, IVFA revealed peripheral areas of an avascular retina. E, R221G proband: multiple inferior chorioretinal atrophic lesions are present with moderate, diffuse atrophy of the optic nerve. The macula is featureless and the retinal vessels are fine and straightened, in keeping with severe retinal dysplasia. The vascular arcade is dragged temporally toward an atrophic scar with a temporal fibrous mass. F, IVFA revealed an area of avascular retina peripheral to the chorioretinal scars and the fibrous mass as well as retinal vascular anomalous formation in the areas without chorioretinal atrophy, resembling what is typically seen in familial exudative vitreoretinopathy with the presence of a fibrovascular mass at the junction of the avascular area.

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