title: Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study.
abstract: BACKGROUND
  Usher syndrome (USH) is an autosomal recessive disorder comprising retinitis pigmentosa, hearing loss and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous with three distinctive clinical types (I-III) and nine Usher genes identified. This study is a comprehensive clinical and genetic analysis of 172 Usher patients and evaluates the contribution of digenic inheritance.
  
  
  METHODS
  The genes MYO7A, USH1C, CDH23, PCDH15, USH1G, USH2A, GPR98, WHRN, CLRN1 and the candidate gene SLC4A7 were sequenced in 172 UK Usher patients, regardless of clinical type.
  
  
  RESULTS
  No subject had definite mutations (nonsense, frameshift or consensus splice site mutations) in two different USH genes. Novel missense variants were classified UV1-4 (unclassified variant): UV4 is 'probably pathogenic', based on control frequency <0.23%, identification in trans to a pathogenic/probably pathogenic mutation and segregation with USH in only one family; and UV3 ('likely pathogenic') as above, but no information on phase. Overall 79% of identified pathogenic/UV4/UV3 variants were truncating and 21% were missense changes. MYO7A accounted for 53.2%, and USH1C for 14.9% of USH1 families (USH1C:c.496+1G>A being the most common USH1 mutation in the cohort). USH2A was responsible for 79.3% of USH2 families and GPR98 for only 6.6%. No mutations were found in USH1G, WHRN or SLC4A7.
  
  
  CONCLUSIONS
  One or two pathogenic/likely pathogenic variants were identified in 86% of cases. No convincing cases of digenic inheritance were found. It is concluded that digenic inheritance does not make a significant contribution to Usher syndrome; the observation of multiple variants in different genes is likely to reflect polymorphic variation, rather than digenic effects.
authors.affiliation: Clinical and Molecular Genetics, Institute of Child Health, UCL, London, UK.
authors.forename: Polona
authors.initials: P
authors.lastname: Le Quesne Stabej
authors.forename: Zubin
authors.initials: Z
authors.lastname: Saihan
authors.forename: Nell
authors.initials: N
authors.lastname: Rangesh
authors.forename: Heather B
authors.initials: HB
authors.lastname: Steele-Stallard
authors.forename: John
authors.initials: J
authors.lastname: Ambrose
authors.forename: Alison
authors.initials: A
authors.lastname: Coffey
authors.forename: Jenny
authors.initials: J
authors.lastname: Emmerson
authors.forename: Elene
authors.initials: E
authors.lastname: Haralambous
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Hughes
authors.forename: Karen P
authors.initials: KP
authors.lastname: Steel
authors.forename: Linda M
authors.initials: LM
authors.lastname: Luxon
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.forename: Maria
authors.initials: M
authors.lastname: Bitner-Glindzicz
mesh_terms: D015331:Cohort Studies; D004252:DNA Mutational Analysis; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D020412:Multifactorial Inheritance; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D006113:United Kingdom; D052245:Usher Syndromes / Q000235:genetics*