Confirmation of the Role of DHX38 in the Etiology of Early-Onset Retinitis Pigmentosa

Abstract

Purpose: Retinitis pigmentosa (RP) is a genetically heterogeneous trait with autosomal-recessive (ar) inheritance underlying 50% of genetic disease cases. Sixty-one arRP genes have been identified, and recently, DHX38 has been reported as a potential candidate gene for arRP with only a single family reported with a variant of unknown significance. We identified a missense variant in DHX38 that co-segregates with the arRP phenotype in two Pakistani families confirming the involvement of DHX38 in the etiology of early-onset RP.

Methods: Exome sequencing was performed using two DNA samples from affected members of Pakistani families (MA88 and MA157) with early onset arRP. Sanger sequencing of DNA samples from all family members confirmed the segregation of candidate variant within both families.

Results: A novel missense DHX38 variant c.971G>A; p.(Arg324Gln) was identified which segregates with the arRP phenotype and yielded a logarithm of the odds (LOD) score of 5.0 and 4.3 for families MA88 and MA157, respectively. This variant is predicted to be conserved and deleterious by several bioinformatics tools.

Conclusions: We identified a second deleterious DHX38 variant that segregates with arRP in two families, providing additional evidence that DHX38 is involved in RP etiology. DHX38 encodes for pre-mRNA splicing factor PRP16, which is important in catalyzing pre-mRNA splicing.

Figure

Genetic and clinical findings for arRP Pakistani families, MA88 and MA157. All individuals from family MA88 with a DNA sample underwent whole-genome genotyping except MA88-5 who was ascertained after genotyping was completed. MA88-3 and MA157-7 were selected to undergo exome sequencing. (A) Fundoscopy images obtained from MA88-11 (20 years old), MA88-8 (19 years old), and MA157-8 (17 years old) display clustered areas of intraretinal pigment on the periphery, macular-atrophy, and attenuation of arteries, while fundoscopy for unaffected MA157-6 (21 years old) was normal. Fundoscopy images for the males who all had bilateral cataracts are not displayed, because it was not possible to view the retina, optic disc, or macula. Pedigree drawing (B) of family MA88 and (C) family MA157. Squares represent males and circles females with filled symbols representing individuals with arRP and clear figures representing unaffected family members. Double lines denote consanguineous marriages. The asterisk symbol (*) above individuals from both families MA88 and MA157 indicates members who were examined and vision tests were performed. Below each family member for which a DNA sample was available is shown their DHX38 c.971G>A genotype.