title: Large genomic rearrangements within the PCDH15 gene are a significant cause of USH1F syndrome.
abstract: OBJECTIVE
  Protocadherin-15 (PCDH15) is one of the five genes currently identified as being mutated in Usher 1 syndrome and defines Usher syndrome type 1F (USH1F). When PCDH15 was systematically analyzed for mutations in a cohort of USH1 patients, a number of deletions were found. Here we characterize these deletions as to extent, position, and breakpoints.
  
  
  METHODS
  Microsatellite and single nucleotide polymorphism (SNP) analyses, used in a preliminary survey of an Usher cohort of 31 patients, revealed large deletions in three patients. These deletions were further characterized by semiquantitative PCR assays to narrow down the breakpoints.
  
  
  RESULTS
  The analysis of the three large deletions revealed that all six breakpoints are different. The breakpoint junction was identified in one patient and the four other breakpoints were mapped to 4 kb. There were no specific distinguishing features of the isolated breakpoints.
  
  
  CONCLUSIONS
  A complete screen of PCDH15 should include a search for large deletions. Failure to screen for gross genomic rearrangements is likely to significantly lower the mutation detection rate. A likely explanation for the high rate of such deletions is the unusual gene structure. PCDH15 gene spans nearly 1 Mb for a corresponding open reading frame (ORF) of 7,021 bp. The intron sizes of PCDH15 are up to 150 kb, and the first three exons of the gene cover 0.42 Mb. The genomic structure of any gene should be taken into consideration when designing a mutation screening strategy.
authors.affiliation: Laboratoire de Génétique Moléculaire du CHU de Montpellier, Institut Universitaire de Recherche Clinique, Montpellier, France.
authors.forename: Sandie
authors.initials: S
authors.lastname: Le Guédard
authors.forename: Valérie
authors.initials: V
authors.lastname: Faugère
authors.forename: Sue
authors.initials: S
authors.lastname: Malcolm
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
authors.forename: Anne-Françoise
authors.initials: AF
authors.lastname: Roux
mesh_terms: D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D017353:Gene Deletion; D015321:Gene Rearrangement; D015894:Genome, Human; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D016133:Polymerase Chain Reaction / Q000379:methods; D052245:Usher Syndromes / Q000235:genetics*
chemical_list: C498835:CDHR15, human; D000070585:Cadherin Related Proteins; D015820:Cadherins