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A missense mutation in the splicing factor gene DHX38 is associated with early-onset retinitis pigmentosa with macular coloboma
  1. Muhammad Ajmal1,2,
  2. Muhammad Imran Khan1,2,
  3. Kornelia Neveling2,
  4. Yar Muhammad Khan1,3,
  5. Maleeha Azam1,2,
  6. Nadia Khalida Waheed4,
  7. Christian P Hamel5,
  8. Tamar Ben-Yosef6,
  9. Elfride De Baere7,
  10. Robert K Koenekoop8,
  11. Rob W J Collin2,9,
  12. Raheel Qamar1,10,
  13. Frans P M Cremers1,2,9
  1. 1Faculty of Science, Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan
  2. 2Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
  3. 3Department of Chemistry, University of Science and Technology, Bannu, Pakistan
  4. 4Department of Ophthalmology, Tufts University School of Medicine, Boston, USA
  5. 5Department of Genetics, Institut National de la Santé et de la Recherche Médicale U, Université Paris Descartes-Sorbonne Paris Cité, Montpellier, France
  6. 6Department of Genetics, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel
  7. 7Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
  8. 8Department of Paediatric Surgery, Human Genetics and Ophthalmology, McGill University Health Centre, Montreal, Canada
  9. 9Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands
  10. 10Al-Nafees Medical College & Hospital, Isra University, Islamabad, Pakistan
  1. Correspondence to Professor Frans PM Cremers, Department of Human Genetics, Radboud University Medical Center, P.O. Box 9101, Nijmegen 6500 HB, The Netherlands; Frans.Cremers{at}


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.

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