RT Journal Article SR Electronic T1 A missense mutation in the splicing factor gene DHX38 is associated with early-onset retinitis pigmentosa with macular coloboma JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 444 OP 448 DO 10.1136/jmedgenet-2014-102316 VO 51 IS 7 A1 Muhammad Ajmal A1 Muhammad Imran Khan A1 Kornelia Neveling A1 Yar Muhammad Khan A1 Maleeha Azam A1 Nadia Khalida Waheed A1 Christian P Hamel A1 Tamar Ben-Yosef A1 Elfride De Baere A1 Robert K Koenekoop A1 Rob W J Collin A1 Raheel Qamar A1 Frans P M Cremers YR 2014 UL http://jmg.bmj.com/content/51/7/444.abstract AB 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.