title: Phenotypic overlap between familial exudative vitreoretinopathy and microcephaly, lymphedema, and chorioretinal dysplasia caused by KIF11 mutations.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.affiliation: 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.
authors.forename: Johane M
authors.initials: JM
authors.lastname: Robitaille
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Roxanne M
authors.initials: RM
authors.lastname: Gillett
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Marissa A
authors.initials: MA
authors.lastname: LeBlanc
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaston
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Mathew
authors.initials: M
authors.lastname: Nightingale
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Mackley
authors.affiliation: Department of Pediatrics, Maritime Medical Genetics Service, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Parkash
authors.affiliation: Providence Health Care Heart Centre, St. Paul's Hospital, Vancouver Coastal Health, Vancouver, British Columbia, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Hathaway
authors.affiliation: Maritime Medical Genetics Service, IWK Health Centre, Halifax, Nova Scotia, Canada.
authors.forename: Aidan
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Department of Surgery, University of Calgary, Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Ells
authors.affiliation: Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Elias I
authors.initials: EI
authors.lastname: Traboulsi
authors.affiliation: Department of Ophthalmology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Elise
authors.initials: E
authors.lastname: Héon
authors.affiliation: Réseau de santé Vitalité Health Network, Hôpital regional Chaleur Regional Hospital, Bathurst, New Brunswick, Canada.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Roy
authors.affiliation: Genetic Institute, Emek Medical Center, Afula, Rappaport School of Medicine, Technion, Haifa, Israel.
authors.forename: Stavit
authors.initials: S
authors.lastname: Shalev
authors.affiliation: Department of Pediatrics, Pediatric Oncology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Conrad V
authors.initials: CV
authors.lastname: Fernandez
authors.affiliation: Department of Ophthalmology, Capital Health, Halifax, Nova Scotia, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: MacGillivray
authors.affiliation: IWK Health Centre Eye Care Team, Halifax, Nova Scotia, Canada2Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Karin
authors.initials: K
authors.lastname: Wallace
authors.affiliation: Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada15Genome Quebec Innovation Center, Montreal, Quebec, Canada.
authors.forename: Somayyeh
authors.initials: S
authors.lastname: Fahiminiya
authors.affiliation: Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada15Genome Quebec Innovation Center, Montreal, Quebec, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McMaster
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Bedard
mesh_terms: D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004594:Electrophysiology; D005091:Exons / Q000235:genetics; D015785:Eye Diseases, Hereditary; D019066:Facies; D000080345:Familial Exudative Vitreoretinopathies; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D008209:Lymphedema / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012164:Retinal Diseases / Q000175:diagnosis / Q000235:genetics; D015792:Retinal Dysplasia / Q000175:diagnosis / Q000235:genetics*
chemical_list: C470243:KIF11 protein, human; D016547:Kinesins