Johane M Robitaille1, Roxanne M Gillett2, Marissa A LeBlanc2, Daniel Gaston2, Mathew Nightingale2, Michael P Mackley2, Sandhya Parkash3, Julie Hathaway4, Aidan Thomas5, Anna Ells6, Elias I Traboulsi7, Elise Héon8, Mélanie Roy9, Stavit Shalev10, Conrad V Fernandez11, Christine MacGillivray12, Karin Wallace13, Somayyeh Fahiminiya14, Jacek Majewski14, Christopher R McMaster15, Karen Bedard2. 1. IWK Health Centre Eye Care Team, Halifax, Nova Scotia, Canada2Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada3Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada. 2. Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada. 3. Department of Pediatrics, Maritime Medical Genetics Service, Dalhousie University, Halifax, Nova Scotia, Canada. 4. Providence Health Care Heart Centre, St. Paul's Hospital, Vancouver Coastal Health, Vancouver, British Columbia, Canada. 5. Maritime Medical Genetics Service, IWK Health Centre, Halifax, Nova Scotia, Canada. 6. Department of Surgery, University of Calgary, Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada. 7. Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio. 8. Department of Ophthalmology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. 9. Réseau de santé Vitalité Health Network, Hôpital regional Chaleur Regional Hospital, Bathurst, New Brunswick, Canada. 10. Genetic Institute, Emek Medical Center, Afula, Rappaport School of Medicine, Technion, Haifa, Israel. 11. Department of Pediatrics, Pediatric Oncology, Dalhousie University, Halifax, Nova Scotia, Canada. 12. Department of Ophthalmology, Capital Health, Halifax, Nova Scotia, Canada. 13. IWK Health Centre Eye Care Team, Halifax, Nova Scotia, Canada2Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada. 14. Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada15Genome Quebec Innovation Center, Montreal, Quebec, Canada. 15. Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Abstract
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.
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.
Authors: Evangelia S Panagiotou; Carla Sanjurjo Soriano; James A Poulter; Emma C Lord; Denisa Dzulova; Hiroyuki Kondo; Atsushi Hiyoshi; Brian Hon-Yin Chung; Yoyo Wing-Yiu Chu; Connie H Y Lai; Mark E Tafoya; Dyah Karjosukarso; Rob W J Collin; Joanne Topping; Louise M Downey; Manir Ali; Chris F Inglehearn; Carmel Toomes Journal: Am J Hum Genet Date: 2017-06-01 Impact factor: 11.025