title: Genomic rearrangements of the PRPF31 gene account for 2.5% of autosomal dominant retinitis pigmentosa.
abstract: OBJECTIVE
  To determine whether genomic rearrangements in the PRPF31 (RP11) gene are a frequent cause of autosomal dominant retinitis pigmentosa (adRP) in a cohort of patients with adRP.
  
  
  METHODS
  In a cohort of 200 families with adRP, disease-causing mutations have previously been identified in 107 families. To determine the cause of disease in the remaining families, linkage testing was performed with markers for 13 known adRP loci. In a large American family, evidence was found of linkage to the PRPF31 gene, although DNA sequencing revealed no mutations. SNP testing throughout the genomic region was used to determine whether any part of the gene was deleted. Aberrant segregation of a SNP near exon 1 was observed, leading to the testing of additional SNPs in the region. After identifying an insertion-deletion mutation, the remaining 92 families were screened for genomic rearrangements in PRPF31 with multiplex ligation-dependent probe amplification (MLPA).
  
  
  RESULTS
  Five unique rearrangements were identified in the 93 families tested. In the large family used for linkage exclusion testing, an insertion-deletion was found that disrupts exon 1. The other four mutations identified in the cohort were deletions, ranging from 5 kb to greater than 45 kb. Two of the large deletions encompass all PRPF31 as well as several adjacent genes. The two smaller deletions involve either 5 or 10 completely deleted exons.
  
  
  CONCLUSIONS
  In an earlier long-term study of 200 families with adRP, disease-causing mutations were identified in 53% of the families. Mutation-testing by sequencing missed large-scale genomic rearrangements such as insertions or deletions. MLPA was used to identify genomic rearrangements in PRPF31 in five families, suggesting a frequency of approximately 2.5%. Mutations in PRPF31 now account for 8% of this adRP cohort.
authors.affiliation: Human Genetics Center, The University of Texas Health Science Center at Houston, TX 77030, USA. lori.s.sullivan@uth.tmc.edu
authors.forename: Lori S
authors.initials: LS
authors.lastname: Sullivan
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Bowne
authors.forename: C Robyn
authors.initials: CR
authors.lastname: Seaman
authors.forename: Susan H
authors.initials: SH
authors.lastname: Blanton
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lewis
authors.forename: John R
authors.initials: JR
authors.lastname: Heckenlively
authors.forename: David G
authors.initials: DG
authors.lastname: Birch
authors.forename: Dianna
authors.initials: D
authors.lastname: Hughbanks-Wheaton
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Daiger
mesh_terms: D000293:Adolescent; D000328:Adult; D004252:DNA Mutational Analysis; D015342:DNA Probes / Q000737:chemistry; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D015321:Gene Rearrangement; D005799:Genes, Dominant; D008040:Genetic Linkage; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D021141:Nucleic Acid Amplification Techniques; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012326:RNA Splicing / Q000235:genetics; D012174:Retinitis Pigmentosa / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D015342:DNA Probes; D005136:Eye Proteins; C454222:PRPF31 protein, human