Exome Sequencing Identifies Novel Gene For Recessive Retinitis Pigmentosa

Abstract

Purpose: : Whole genome approaches, such as exome sequencing, have the potential to revolutionize gene identification in familial disorders that were thought to be intractable. We have applied whole exome sequencing to a family with apparent autosomal recessive (AR) retinitis pigmentosa (RP). RP comprises a large number of genetically distinct forms of inherited degeneration of the retina leading to progressive loss of vision. Over 40 non-syndromic RP genes and chromosomal loci have been mapped thus far, yet they explain only ~50% of the genetic risk. The remaining genes likely represent rare forms with only few families affected worldwide.

Methods: : We performed whole exome sequencing in three affected and one unaffected siblings of an Ashkenazi Jewish (AJ) RP family that screened negative for all known AR RP mutations.

Results: : Across the four individuals we identified 19,307 coding single nucleotide variants. In all, 238 significant variants, including 27 indels, co-segregated with the phenotype, but only one change was novel (i.e. not reported in dbSNP) in the gene, dehydrodolichol diphosphate synthase (DHDDS). DHDDS is a highly conserved essential enzyme for dolichol synthesis permitting global N-linked glycosylation. Zebrafish studies showed virtually identical photoreceptor defects as observed with N-linked glycosylation-interfering mutations in the light sensing protein rhodopsin. The identified K42E mutation likely arose from an ancestral founder as eight of the nine identified alleles in 27,174 control chromosomes were of confirmed Ashkenazi Jewish ethnicity. Both parents carried the ancestral haplotype.

Conclusions: : In summary, we demonstrate the first gene identification (DHDDS) in a single small human recessive family suffering from a genetically highly heterogeneous phenotype. These results emphasize both the value of the whole genome approach as well as link RP to the pathways of N-linked glycosylation, which promise new avenues for therapeutic interventions.

Keywords: retinal degenerations: hereditary • genetics • clinical (human) or epidemiologic studies: risk factor assessment