title: A Nonsense Mutation in FAM161A Is a Recurrent Founder Allele in Dutch and Belgian Individuals With Autosomal Recessive Retinitis Pigmentosa.
abstract: OBJECTIVE
  To identify mutations in FAM161A underlying autosomal recessive retinitis pigmentosa (arRP) in the Dutch and Belgian populations and to investigate whether common FAM161A-associated phenotypic features could be identified.
  
  
  METHODS
  Homozygosity mapping, amplification-refractory mutation system (ARMS) analysis, and Sanger sequencing were performed to identify mutations in FAM161A. Microsatellite and SNP markers were genotyped for haplotype analysis. Patients with biallelic mutations underwent detailed ophthalmologic examinations, including measuring best-corrected visual acuity, extensive fundus photography with reflectance and autofluorescence imaging, and optical coherence tomography.
  
  
  RESULTS
  Homozygosity mapping in 230 Dutch individuals with suspected arRP yielded five individuals with a homozygous region harboring FAM161A. Sanger sequencing revealed a homozygous nonsense mutation (c.1309A>T; p.[Arg437*]) in one individual. Subsequent ARMS analysis and Sanger sequencing in Dutch and Belgian arRP patients resulted in the identification of seven additional individuals carrying the p.(Arg437*) mutation, either homozygously or compound heterozygously with another mutation. Haplotype analysis identified a shared haplotype block of 409 kb surrounding the p.(Arg437*) mutation in all patients, suggesting a founder effect. Although the age of onset was variable among patients, all eight developed pronounced outer retinal loss with severe visual field defects and a bull's eye-like maculopathy, followed by loss of central vision within 2 decades after the initial diagnosis in five subjects.
  
  
  CONCLUSIONS
  A founder mutation in FAM161A p.(Arg437*) underlies approximately 2% of arRP cases in the Dutch and Belgian populations. The age of onset of the retinal dystrophy appears variable, but progression can be steep, with almost complete loss of central vision later in life.
authors.affiliation: Center for Medical Genetics Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Kristof
authors.initials: K
authors.lastname: Van Schil
authors.affiliation: Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands 3Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: B Jeroen
authors.initials: BJ
authors.lastname: Klevering
authors.affiliation: Center for Medical Genetics Ghent University and Ghent University Hospital, Ghent, Belgium 4Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium 5Division of Ophthalmology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Bart P
authors.initials: BP
authors.lastname: Leroy
authors.affiliation: Department of Ophthalmology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Jan Willem R
authors.initials: JW
authors.lastname: Pott
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Dikla
authors.initials: D
authors.lastname: Bandah-Rozenfeld
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marijke N
authors.initials: MN
authors.lastname: Zonneveld-Vrieling
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Sharon
authors.affiliation: Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands 8Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands 9Radboud Institute for Molecular Life Sciences, Radboud University Medica.
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands 9Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.affiliation: Center for Medical Genetics Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Elfride
authors.initials: E
authors.lastname: De Baere
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands 9Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Rob W J
authors.initials: RW
authors.lastname: Collin
authors.affiliation: The Rotterdam Eye Hospital, Rotterdam, The Netherlands.
authors.forename: L Ingeborgh
authors.initials: LI
authors.lastname: van den Born
mesh_terms: D000328:Adult; D000483:Alleles; D001530:Belgium / Q000453:epidemiology; D018389:Codon, Nonsense; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005808:Genes, Recessive; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009426:Netherlands / Q000453:epidemiology; D010375:Pedigree; D012174:Retinitis Pigmentosa / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; D005136:Eye Proteins; C552553:FAM161A protein, human; D004247:DNA