title: A missense mutation in the splicing factor gene DHX38 is associated with early-onset retinitis pigmentosa with macular coloboma.
abstract: BACKGROUND
  Retinitis pigmentosa (RP) is the most frequent inherited retinal disease, which shows a relatively high incidence of the autosomal-recessive form in Pakistan.
  
  
  METHODS
  Genome-wide high-density single-nucleotide polymorphism (SNP) microarrays were used to identify homozygous regions shared by affected individuals of one consanguineous family. DNA of three affected and two healthy siblings was used for SNP genotyping. Genotyping data were then analysed by Homozygosity Mapper. DNA of the proband was further analysed employing exome sequencing.
  
  
  RESULTS
  Homozygosity mapping revealed a single homozygous region on chromosome 16, shared by three affected individuals. Subsequent exome sequencing identified a novel missense mutation, c.995G>A; p.(Gly332Asp), in DHX38. This mutation was found to be present in a homozygous state in four affected individuals while two healthy siblings and the parents of the affected persons were heterozygous for this mutation. This variant thereby yields a logarithm of the odds (LOD) score of 3.25, which is highly suggestive for linkage. This variant was neither detected in 180 ethnically matched control individuals, nor in 7540 Africans or Caucasians and an in-house database that contained the exome data of 400 individuals.
  
  
  CONCLUSIONS
  By combining genome-wide homozygosity mapping and exome sequencing, a novel missense mutation was identified in the DHX38 gene that encodes the pre-mRNA splicing factor PRP16, in a Pakistani family with early-onset autosomal-recessive RP. The phenotype is different from those associated with other retinal pre-mRNA splicing factors and DHX38 is the first pre-mRNA splicing gene that is putatively associated with autosomal-recessive inherited RP.
authors.affiliation: Faculty of Science, Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ajmal
authors.affiliation: Faculty of Science, Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Muhammad Imran
authors.initials: MI
authors.lastname: Khan
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Neveling
authors.affiliation: Faculty of Science, Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan Department of Chemistry, University of Science and Technology, Bannu, Pakistan.
authors.forename: Yar Muhammad
authors.initials: YM
authors.lastname: Khan
authors.affiliation: Faculty of Science, Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Maleeha
authors.initials: M
authors.lastname: Azam
authors.affiliation: Department of Ophthalmology, Tufts University School of Medicine, Boston, USA.
authors.forename: Nadia Khalida
authors.initials: NK
authors.lastname: Waheed
authors.affiliation: Department of Genetics, Institut National de la Santé et de la Recherche Médicale U, Université Paris Descartes-Sorbonne Paris Cité, Montpellier, France.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Hamel
authors.affiliation: Department of Genetics, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Ben-Yosef
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Elfride
authors.initials: E
authors.lastname: De Baere
authors.affiliation: Department of Paediatric Surgery, Human Genetics and Ophthalmology, McGill University Health Centre, Montreal, Canada.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: Rob W J
authors.initials: RW
authors.lastname: Collin
authors.affiliation: Faculty of Science, Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan Al-Nafees Medical College & Hospital, Isra University, Islamabad, Pakistan.
authors.forename: Raheel
authors.initials: R
authors.lastname: Qamar
authors.affiliation: Faculty of Science, Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
mesh_terms: D001483:Base Sequence; D003103:Coloboma / Q000235:genetics*; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive; D056726:Genetic Association Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D008266:Macula Lutea / Q000002:abnormalities*; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D000072260:RNA Splicing Factors; D012174:Retinitis Pigmentosa / Q000235:genetics*
chemical_list: D000072260:RNA Splicing Factors; C112199:DHX38 protein, human; D053487:DEAD-box RNA Helicases