title: Whole exome sequencing of a dominant retinitis pigmentosa family identifies a novel deletion in PRPF31.
abstract: OBJECTIVE
  Mutations at some retinitis pigmentosa (RP) loci are associated with variable penetrance and expressivity, exacerbating diagnostic challenges. The purpose of this study was to dissect the genetic underpinnings of nonsyndromic RP with variable age of onset in a large Mexican family.
  
  
  METHODS
  We ascertained members of a large, multigenerational pedigree using a complete ophthalmic examination. We performed whole exome sequencing on two affected first cousins, an obligate carrier, and a married-in spouse. Confirmatory sequencing of candidate variants was performed in the entire pedigree, as well as genotyping and mRNA studies to investigate expression changes in the causal locus.
  
  
  RESULTS
  We identified a 14-base pair (bp) deletion in PRPF31, a gene implicated previously in autosomal dominant (ad) RP. The mutation segregated with the phenotype of all 10 affected females, but also was present in six asymptomatics (two females and four males). Studies in patient cells showed that the penetrance/expressivity of the PRPF31 deletion allele was concordant with the expression levels of wild-type message. However, neither the known PRPF31 modulators nor cis-eQTLs within 1 Mb of the locus could account for the variable expression of message or the clinical phenotype.
  
  
  CONCLUSIONS
  We have identified a novel 14-bp deletion in PRPF31 as the genetic driver of adRP in a large Mexican family that exhibits nonpenetrance and variable expressivity, known properties of this locus. However, our studies intimate the presence of additional loci that can modify PRPF31 expression.
authors.affiliation: Virtual Eye Care MD, Mérida, Yucatán, México.
authors.forename: Adda
authors.initials: A
authors.lastname: Villanueva
authors.forename: Jason R
authors.initials: JR
authors.lastname: Willer
authors.forename: Julien
authors.initials: J
authors.lastname: Bryois
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Erica E
authors.initials: EE
authors.lastname: Davis
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D059472:Exome / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics*; D012326:RNA Splicing; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: D005136:Eye Proteins; C454222:PRPF31 protein, human; D012313:RNA
keywords: PRPF31; autosomal dominant; exome sequencing; genetic diseases; retinitis pigmentosa