title: The Genetic Causes of Nonsyndromic Congenital Retinal Detachment: A Genetic and Phenotypic Study of Pakistani Families.
abstract: To evaluate consanguineous pedigrees from Pakistan with a clinical diagnosis of nonsyndromic congenital retinal nonattachment (NCRNA) and identify genes responsible for the disease as currently only one NCRNA gene is known (atonal basic helix-loop-helix transcription factor 7: ATOH7).
  
  
  
  We implemented a three-step genotyping platform: single nucleotide polymorphism genotyping to identify loss of heterozygosity regions in patients, Retinal Information Network panel screening for mutations in currently known retinal genes. Negative patients were then subjected to whole exome sequencing.
  
  
  
  We evaluated 21 consanguineous NCRNA pedigrees and identified the causal mutations in known retinal genes in 13 out of our 21 families. We found mutations in ATOH7 in three families. Surprisingly, we then found mutations in familial exudative vitreoretinopathy (FEVR) genes; low-density lipoprotein receptor-related protein 5 mutations (six families), tetraspanin 12 mutations (two families), and NDP mutations (two families). Thus, 62% of the patients were successfully genotyped in our study with seven novel and six previously reported mutations in known retinal genes.
  
  
  
  Although the clinical diagnosis of all children was NCRNA with severe congenital fibrotic retinal detachments, the molecular diagnosis determined that the disease process was in fact a very severe form of FEVR in 10 families. Because severe congenital retinal detachment has not been previously associated with all the FEVR genes, we have thus expanded the phenotypic spectrum of FEVR, a highly variable retinal detachment phenotype that has clinical overlap with NCRNA. We identified seven novel mutations. We also established for the first time genetic overlap between the Iranian and Pakistani populations. We identified eight NCRNA families that do not harbor mutations in any known retinal genes, suggesting novel causal genes in these families.
authors.affiliation: McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Vafa
authors.initials: V
authors.lastname: Keser
authors.affiliation: McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Khan
authors.affiliation: McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Sorath
authors.initials: S
authors.lastname: Siddiqui
authors.affiliation: McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Irma
authors.initials: I
authors.lastname: Lopez
authors.affiliation: McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Huanan
authors.initials: H
authors.lastname: Ren
authors.affiliation: Department of Pediatric Ophthalmology, Al Shifa Trust Eye Hospital, Rawalpindi, Pakistan.
authors.forename: Raheel
authors.initials: R
authors.lastname: Qamar
authors.affiliation: Quebec Genome Centre, Montreal, Quebec, Canada.
authors.forename: Javad
authors.initials: J
authors.lastname: Nadaf
authors.affiliation: Quebec Genome Centre, Montreal, Quebec, Canada 4Faculty of Medicine, Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D015994:Incidence; D007223:Infant; D008297:Male; D009154:Mutation; D010154:Pakistan / Q000453:epidemiology; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012160:Retina / Q000378:metabolism*; D012164:Retinal Diseases / Q000151:congenital* / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C456975:ATOH7 protein, human