title: Whole exome sequencing reveals GUCY2D as a major gene associated with cone and cone-rod dystrophy in Israel.
abstract: OBJECTIVE
  The Israeli population has a unique genetic make-up, with a high prevalence of consanguineous marriages and autosomal recessive diseases. In rod-dominated phenotypes, disease-causing genes and mutations that differ from those identified in other populations often are incurred. We used whole exome sequencing (WES) to identify genetic defects in Israeli families with cone-dominated retinal phenotypes.
  
  
  METHODS
  Clinical analysis included family history, detailed ocular examination, visual function testing, and retinal imaging. Whole exome sequencing, followed by segregation analysis, was performed in 6 cone-dominated retinopathy families in which prior mutation analysis did not reveal the causative gene. Based on the WES findings, we screened 106 additional families with cone-dominated phenotypes.
  
  
  RESULTS
  The WES analysis revealed mutations in known retinopathy genes in five of the six families: two pathogenic mutations in the GUCY2D gene in three families, and one each in CDHR1 and C8orf37. Targeted screening of additional cone-dominated families led to identification of GUCY2D mutations in four other families, which included two highly probable novel disease-causing variants.
  
  
  CONCLUSIONS
  Our study suggested that GUCY2D is a major cause of autosomal dominant cone and cone-rod dystrophies in Israel; this is similar to other Caucasian populations and is in contrast with retinitis pigmentosa (primary rod disease), where the genetic make-up of the Israeli population is distinct from other ethnic groups. We also conclude that WES permits more comprehensive and rapid analyses that can be followed by targeted screens of larger samples to delineate the genetic structure of retinal disease in unique population cohorts.
authors.affiliation: Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States Molecular Biology Center, Interdisciplinary Research Institute on Bio-Nano Sciences, Babes-Bolyai-University, Cluj-Napoca, Romania.
authors.forename: Csilla H
authors.initials: CH
authors.lastname: Lazar
authors.affiliation: Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, India.
authors.forename: Mousumi
authors.initials: M
authors.lastname: Mutsuddi
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Adva
authors.initials: A
authors.lastname: Kimchi
authors.affiliation: Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Lina
authors.initials: L
authors.lastname: Zelinger
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Liliana
authors.initials: L
authors.lastname: Mizrahi-Meissonnier
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Devorah
authors.initials: D
authors.lastname: Marks-Ohana
authors.affiliation: Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States.
authors.forename: Alexis
authors.initials: A
authors.lastname: Boleda
authors.affiliation: Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States.
authors.forename: Rinki
authors.initials: R
authors.lastname: Ratnapriya
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Sharon
authors.affiliation: Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States.
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
authors.affiliation: Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Banin
mesh_terms: D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004596:Electroretinography; D059472:Exome; D005260:Female; D006162:Guanylate Cyclase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007557:Israel / Q000453:epidemiology; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D015995:Prevalence; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology
chemical_list: D011956:Receptors, Cell Surface; C110715:guanylate cyclase 1; D004247:DNA; D006162:Guanylate Cyclase
keywords: inherited blindness; next generation sequencing; photoreceptor degeneration